Methods, compositions, and uses of novel Fyn kinase inhibitors

ABSTRACT

The present invention provides methods for inhibiting Fyn kinase, using 5-3-pyridin-2-amine, 6-3-imidazo[1,2-a] pyrazine, 6-3-imidazo[1,2-b] pyridazine, N-(5-imidazo [2,1-b][1,3,4] thiadiazol-2-yl)-amine, 4-3-1H-pyrazolo[3,4-b] pyridine, and N-(3-imidazo [1,2-b] pyridazin-6-yl) amine compounds and methods of treatment, prevention, inhibition or amelioration of diseases and conditions associated with Fyn kinase using such compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is the 35 U.S.C. 371 National Stage ofInternational Application Number PCT/US2016/050776, filed Sep. 8, 2016,which claims priority from U.S. Provisional Patent Application No.62/216,349 filed Sep. 9, 2015, the contents of each of which areincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to methods for inhibiting, regulating ormodulating the activity of Fyn kinase, using compounds or pharmaceuticalcompositions containing such compounds and methods of treatment usingthe compounds or compositions to treat diabetes, pre-diabetes, metabolicconditions, immune disorders, cancer and neurodegenerative disorderssuch as Multiple Sclerosis. Alzheimer's and Parkinson's disease.

BACKGROUND OF THE INVENTION

Fyn kinase, a cytoplasmic Src family tyrosine kinase, plays an importantrole in many physiologic processes and is ubiquitous in human cells. Fynkinase is primarily found on the cytoplasmic face of the plasma membranewhere it phosphorylates tyrosine residues of a number of differentenzymes involved in the signaling pathways associated with variouscell-surface receptors. Fyn kinase is involved in cellular development,apoptosis, and homeostatic regulation, as well as in the development ofmany different kinds of pathologies. Fyn kinase represents an attractivetarget for drug therapies designed to control cellular metabolism formanagement of diabetes, pre-diabetes and general weight lossapplications, as an anti-cancer therapeutic and as potential target forthe control or prevention of Multiple Sclerosis, Alzheimer's andParkinson's disease.

Fyn knockout mice exhibit increased lipid utilization and increasedenergy expenditure. Wild-type mice treated with the highly selective Srcfamily kinase inhibitor SU6656, exhibit similar increases in lipidutilization and energy utilization, whereas the Fyn knockout strainsshow no increase in either parameter upon treatment with SU6656 (WO2011/119199). Both the Fyn knockout and SU6656 treated mice havesignificantly reduced fat mass relative to untreated or geneticallymatched Fyn-competent control mice. Treatment with SU6656 appears toreduce adiposity and promote weight loss, likely through aFyn-kinase-dependent mechanism.

Fyn kinases ability to regulate fatty acid oxidation and increase energyexpenditure is thought to result from its affect on sequestration ofLKB1 to the nucleus of skeletal muscle cells. Fyn kinase phosphorylatesLKB1 present in the cytoplasm of such cells and the phosphorylated LKB1is preferentially localized to the nucleus where it has little or noaccess to AMPK, which is found almost exclusively in the cytoplasm.Thus, LKB1 phosphorylated by Fyn kinase cannot activate AMPK(AMP-dependent protein kinase). Activated AMPK serves as a cellularenergy sensor directly regulated by alterations in the intracellularAMP/ATP ratio that occurs during prolonged fasting and re-feeding. Athigh AMP/ATP ratios activation of AMPK results in phosphorylation andinhibition of Acetyl CoA Carboxylase, thereby increasing fatty acidoxidation and decreasing fatty acid biosynthesis. Specific inhibition ofFyn kinase allows LKB1 to constitutively activate AMPK. In this modelinhibition of Fyn kinase results in increased cytoplasmic localizationof LKB1, resulting in increased levels of activated AMPK.

AMPK also regulates glucose metabolism in liver. Hepatic glucoseproduction that is not regulated by insulin is known to play animportant role in development of Type 2 diabetes. The asymptomaticinsulin resistance phase of Type 2 diabetes is generally followed bydefects in insulin secretion that result in severe hyperglycemia if leftuntreated. Chronic high glucose levels have been shown to result in thedeath of pancreatic n-cells and loss of insulin production altogether.Activated AMPK reduces insulin secretion and is thought to have apro-apoptotic effect on pancreatic β-cells.

Like many Src family kinases, Fyn plays a role in regulating severalphysiological processes including cellular growth, proliferation,morphogenesis and motility. Fyn has also been recognized as a potentialoncogene and has been shown to be capable of inducing the fullytumorigenic phenotype. Fyn interacts with a number of cancer relatedpathways. Fyn is a mediator of growth-factor induced anti-apoptoticactivity of Akt/PKB, and regulates Rac and Rho GTPases and activates theERK/MAPK pathways. Fyn also plays a key role in the regulation of matrixformation and degradation, which is important for matrix remodeling andcellular adherence.

In addition to metabolic and oncogenic regulation, Fyn is recognized asplaying a key role in T-cell development as well as dendritic maturationof cells within the central nervous system. Further, inhibition of Fynkinase is viewed as an attractive therapeutic target for treatment ofMultiple Sclerosis. Alzheimer's and Parkinson's disease. It is theobject of this disclosure to describe pharmaceutically effectiveinhibitors of Fyn kinase with enhanced specificity for therapeutictreatment of one or more of the pathologies in which Fyn kinase plays arole.

Structurally, Fyn kinase is relatively well characterized despite thelack of a complete high-resolution structure. The enzyme comprises 537amino acids in a single polypeptide chain organized into 4 domains, witha molecular weight of 59 kilodaltons. The N-terminal membrane anchoringdomain (SH4) possesses myristylated or palmitylated residues essentialfor proper enzyme trafficking and localization to the cytoplasmicmembrane, immediately adjacent to this are the SH3 and SH2 domains,which play critical roles in the interaction of Fyn kinase with itsprotein targets, followed by a flexible linker connecting the C-terminaltyrosine kinase domain (SH1). Although a complete high-resolutionstructure of the entire Fyn kinase protein is not available, suchstructures are available for each of the SH2, 3 and 4 domains,individually.

The SH2 domain of Fyn kinase binds phosphotyrosine-containing sequencesand functions as a target recognition domain. The SH3 domainpromiscuously complexes with polyproline peptides and plays a role inmediating protein-protein interactions between Fyn kinase and otherpolypeptides. Interaction between the SH3 and SH2 domains enhances thespecificity of ligand binding and regulates the activity of the kinase(SH4) domain.

The well conserved SH4 domain contains two potential inhibitor bindingsites, the first, sensitive to non-specific competitive inhibitors ofATP such as staurosporine, represents the actual ATP binding site of thekinase domain, whereas the second site, immediately adjacent to the ATPbinding pocket, is oriented towards the SH2 domain. This second site maybe occupied in such a way that ATP binding at the first site is notdirectly blocked. However, free access to the second site is blocked bythe presence of ATP at the first site, and hence, inhibitors targeted tothe second site display pseudo-competitive kinetics with respect to theavailability of ATP. Although the ATP binding site is highly conservedamong Src kinases, the amino acids comprising the hydrophobic pockettypical of the second site are less conserved and may represent the besttarget for Fyn-specific inhibitors. Regardless, the SH1 domain isessential for the activity of Fyn kinase on any of its protein targets,and has been targeted for the development of potent Fyn kinaseinhibitors.

Existing Fyn kinase inhibitors all suffer from a lack of specificity andalthough many Fyn kinase inhibitors have been isolated, mostsignificantly cross-react with other Src family enzymes. Some of thebest known Fyn kinase inhibitors include: phenolic compounds such asrosmarinic acid, (−)-epigallocatechin gallate and myricetin; thepyrazolol[3,4-d] pyrimidines PP1, PP2, and various derivatives thereof;as well as other fused pyrimidine compounds such as benzyl21-methoxy-5,7,19-trioxa-2,13,24,26-tetraazapentacyclo[18.6.2.0^(3,11)0.0^(4,8)0.0^(23,2) ⁷]octacosa-1(26),3(11),4(8),9,20,22,24,27-octaene-13-carboxylate (JanssenPharmaceuticals, U.S. Pat. No. 8,492,377) and CT5263 and CT5102(CellTech). The structure of a few of these compounds and theirassociated IC50 (when known) and log P values are presented in Table 1.

TABLE 1 Known Fyn kinase inhibitors. IC50 logP FYN (con- CommonStructure IUPAC name (μM) sensus) name

(2R)-3-(3,4-dihydroxy- phenyl)-2-{[(2E)-3-(3,4- dihydroxyphenyl)prop-2-enoyl]oxy} propanoic acid 1.3   3.00 rosmarinic acid

(2R,3R)-5,7-dihydroxy- 2-(3,4,5-trihydroxy- phenyl)-3,4-dihydro-2H-1-benzopyran-3-yl 3,4,5 unknown 3.08 (−)-epigallo- catechin gallate

5,7-dihydroxy-2-(3,4,5- trihydroxyphenyl)-4H- chromen-4-one unknown 0.65myricetin

1-tert-butyl-3-(4- methylphenyl)-1H- pyrazolo[3,4-d] pyrimidin-4-amine0.006  3.23 PP1 (Pfizer)

1-tert-butyl-3-(4- chlorophenyl)-1H- pyrazolo[3,4-d] pyrimidin-4-amine0.006  3.32 PP2 (Pfizer)

N-(4-{4-amino-1- [(1r,4r)-4-(4-methyl- piperazin-1-yl)cyclo-hexyl]-1H-pyrazolo [3,4-d]pyrimidin-3- yl}-2-methoxy-phenyl)-1-methyl-1H- indole-2-carboxamide 0.330  3.81 A-420983 (Abbott)

benzyl- 21-methoxy-5,7,19- trioxa-2,13,24,26- tetraazapenta-cyclo[18.6.2.0³, ¹¹.0⁴,⁸.0²³,² ⁷ ]octacosa- 1(26),3(11),4(8),9,20,22,24,27-octaene- 13-carboxylate 0.00669 5.13 Compound B50 (U.S. Pat.No. 8,492,377) (Janssen Pharma- ceuticals)

9-methoxy-N-{3- methoxy-4-[3- (pyrrolidin-1-yl)propyl]phenyl}-6,6-dimethyl- 5H,6H-benzo[h] quinazolin-2-amine 0.008  6.12CT5263 (CellTech)

N-{4-[2-(dimethyl- amino)ethoxy]- 3,5-dimethyl phenyl}-9-methoxy-5H,6H-benzo[h] quinazolin-2-amine 0.008  5.49 CT5102 (CellTech)

SUMMARY OF THE INVENTION

Among its many embodiments, the present invention comprises methods forinhibiting Fyn kinase using 5-[R2]-3-[R1] pyridin-2-amine compounds orpharmaceutical compositions comprising such compounds and methods oftreatment, prevention, inhibition or amelioration of one or more of thediseases or conditions associated with Fyn kinase.

In one aspect, the present invention provides a method of inhibiting Fynkinase in a patient, the method comprising administering atherapeutically effective amount of at least one compound, or apharmaceutically acceptable salt or solvate of the compound to a patientin need thereof, the compound being 5-[R2]-3-[R1] pyridin-2-amine,wherein R1 and R2 are each individually selected from the groupconsisting of H, alkyl, alkenyl, alkylene, alkynyl, aryl, arylalkyl,alkylaryl, arylalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,cycloalkenylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, heterocyclenyl, wherein each of the alkyl, alkenyl,alkylene, alkynyl, alkynylalkyl, aryl, arylalkyl, alkylaryl,arylalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,cycloalkenylalkyl, heterocyclic moieties can be substituted with one ormore moieties which can be the same or different, each moiety beingindependently selected from the group consisting of acyl, alcohol,alkyl, aryl, aroyl, alkoxy, aryloxy, arylalkyloxy, alkylthio, arylthio,aralkylthio, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,alkylsulfonyl, arylsulfonyl, cyano, hydroxyalkyl, amide, amine, thiol,thiophene, pyrrole, furan, alkylsulfate, arylsulfate, alkylphosphate andarylphosphate.

In another aspect, the present invention provides a method of inhibitingFyn kinase in a patient, the method comprising administering atherapeutically effective amount of at least one compound, or apharmaceutically acceptable salt or solvate of the compound to a patientin need thereof, the compound being one of the 5-[R2]-3-[R1]pyridin-2-amine derivatives of Tables 3 and 4.

In another aspect, the present invention provides a method of treating,or slowing progression of a disease associated with Fyn kinase, themethod comprising administering a therapeutically effective amount of atleast one compound, or a pharmaceutically acceptable salt or solvate ofthe compound to a patient in need thereof, the compound being at leastone of the 5-[R2]-3-[R1] pyridin-2-amines described above, or apharmaceutically acceptable salt or solvate thereof.

In another embodiment, the present invention comprises methods forinhibiting Fyn kinase using 4-[R2]-3-[R1] imidazo[1,2-a] pyrazinecompounds or pharmaceutical compositions comprising such compounds andmethods of treatment, prevention, inhibition or amelioration of one ormore of the diseases or conditions associated with Fyn kinase.

In one aspect, the present invention provides a method of inhibiting Fynkinase in a patient, the method comprising administering atherapeutically effective amount of at least one compound, or apharmaceutically acceptable salt or solvate of the compound to a patientin need thereof, the compound being 6-[R2]-3-[R1] imidazo[1,2-a]pyrazine, wherein R1 and R2 are each individually selected from thegroup consisting of H, alkyl, alkenyl, alkylene, alkynyl, aryl,arylalkyl, alkylaryl, arylalkenyl, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, heterocyclylalkyl, heterocyclenyl, wherein each of thealkyl, alkenyl, alkylene, alkynyl, alkynylalkyl, aryl, arylalkyl,alkylaryl, arylalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,cycloalkenylalkyl, heterocyclic moieties can be substituted with one ormore moieties which can be the same or different, each moiety beingindependently selected from the group consisting of acyl, alcohol,alkyl, aryl, aroyl, alkoxy, aryloxy, arylalkyloxy, alkylthio, arylthio,aralkylthio, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,alkylsulfonyl, arylsulfonyl, cyano, hydroxyalkyl, amide, amine, thiol,thiophene, pyrrole, furan, alkylsulfate, arylsulfate, alkylphosphate andarylphosphate.

In another aspect, the present invention provides a method of inhibitingFyn kinase in a patient, the method comprising administering atherapeutically effective amount of at least one compound, or apharmaceutically acceptable salt or solvate of the compound to a patientin need thereof, the compound being one of the 6-[R2]-3-[R1]imidazo[1,2-a] pyrazine derivatives of Tables 3 and 4.

In another aspect, the present invention provides a method of treating,or slowing progression of a disease associated with Fyn kinase, themethod comprising administering a therapeutically effective amount of atleast one compound, or a pharmaceutically acceptable salt or solvate ofthe compound to a patient in need thereof, the compound being at leastone of the 6-[R2]-3-[R1] imidazo[1,2-a] pyridines described above, or apharmaceutically acceptable salt or solvate thereof.

In another embodiment, the present invention comprises methods forinhibiting Fyn kinase using 6-[R2]-3-[R1] imidazo[1,2-b] pyridazinecompounds or pharmaceutical compositions comprising such compounds andmethods of treatment, prevention, inhibition or amelioration of one ormore of the diseases or conditions associated with Fyn kinase.

In one aspect, the present invention provides a method of inhibiting Fynkinase in a patient, the method comprising administering atherapeutically effective amount of at least one compound, or apharmaceutically acceptable salt or solvate of the compound to a patientin need thereof, the compound being 6-[R2]-3-[R1] imidazo [1,2-b]pyridazine, wherein R1 and R2 are each individually selected from thegroup consisting of H, alkyl, alkenyl, alkylene, alkynyl, aryl,arylalkyl, alkylaryl, arylalkenyl, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, heterocyclylalkyl, heterocyclenyl, wherein each of thealkyl, alkenyl, alkylene, alkynyl, alkynylalkyl, aryl, arylalkyl,alkylaryl, arylalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,cycloalkenylalkyl, heterocyclic moieties can be substituted with one ormore moieties which can be the same or different, each moiety beingindependently selected from the group consisting of acyl, alcohol,alkyl, aryl, aroyl, alkoxy, aryloxy, arylalkyloxy, alkylthio, arylthio,aralkylthio, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,alkylsulfonyl, arylsulfonyl, cyano, hydroxyalkyl, amide, amine, thiol,thiophene, pyrrole, furan, alkylsulfate, arylsulfate, alkylphosphate andarylphosphate.

In another aspect, the present invention provides a method of inhibitingFyn kinase in a patient, the method comprising administering atherapeutically effective amount of at least one compound, or apharmaceutically acceptable salt or solvate of the compound to a patientin need thereof, the compound being one of the 6-[R2]-3-[R1] imidazo[1,2-b] pyridazine derivatives of Tables 3 and 4.

In another aspect, the present invention provides a method of treating,or slowing progression of a disease associated with Fyn kinase, themethod comprising administering a therapeutically effective amount of atleast one compound, or a pharmaceutically acceptable salt or solvate ofthe compound to a patient in need thereof, the compound being at leastone of the 6-[R2]-3-[R1] imidazo [1,2-b] pyridoxines described above, ora pharmaceutically acceptable salt or solvate thereof.

In another embodiments, the present invention comprises methods forinhibiting Fyn kinase using N-(5-[R2] imidazo [2,1-b][1,3,4]thiadiazol-2-yl)[R1]-amine compounds or pharmaceutical compositionscomprising such compounds and methods of treatment, prevention,inhibition or amelioration of one or more of the diseases or conditionsassociated with Fyn kinase.

In one aspect, the present invention provides a method of inhibiting Fynkinase in a patient, the method comprising administering atherapeutically effective amount of at least one compound, or apharmaceutically acceptable salt or solvate of the compound to a patientin need thereof, the compound being N-(5-[R2]imidazo[2,1-b][1,3,4]thiadiazol-2-yl)[R1]-amine, wherein R1 and R2 are each individuallyselected from the group consisting of H, alkyl, alkenyl, alkylene,alkynyl, aryl, arylalkyl, alkylaryl, arylalkenyl, cycloalkyl,cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclenyl,wherein each of the alkyl, alkenyl, alkylene, alkynyl, alkynylalkyl,aryl, arylalkyl, alkylaryl, arylalkenyl, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, heterocyclic moieties can besubstituted with one or more moieties which can be the same ordifferent, each moiety being independently selected from the groupconsisting of acyl, alcohol, alkyl, aryl, aroyl, alkoxy, aryloxy,arylalkyloxy, alkylthio, arylthio, aralkylthio, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, cyano,hydroxyalkyl, amide, amine, thiol, thiophene, pyrrole, furan,alkylsulfate, arylsulfate, alkylphosphate and arylphosphate.

In another aspect, the present invention provides a method of inhibitingFyn kinase in a patient, the method comprising administering atherapeutically effective amount of at least one compound, or apharmaceutically acceptable salt or solvate of the compound to a patientin need thereof, the compound being one of theN-(5-[R2]imidazo[2,1-b][1,3,4] thiadiazol-2-yl)[R1]-amine derivatives ofTables 3 and 4.

In another aspect, the present invention provides a method of treating,or slowing progression of a disease associated with Fyn kinase, themethod comprising administering a therapeutically effective amount of atleast one compound, or a pharmaceutically acceptable salt or solvate ofthe compound to a patient in need thereof, the compound being at leastone of the N-(5-[R2] imidazo [2,1-b] [1,3,4] thiadiazol-2-yl)[R1]-amines described above, or a pharmaceutically acceptable salt orsolvate thereof.

In another embodiment, the present invention comprises methods forinhibiting Fyn kinase using 4-[R2]-3-[R1]-1H-pyrazolo[3,4-b] pyridinecompounds or pharmaceutical compositions comprising such compounds andmethods of treatment, prevention, inhibition or amelioration of one ormore of the diseases or conditions associated with Fyn kinase.

In one aspect, the present invention provides a method of inhibiting Fynkinase in a patient, the method comprising administering atherapeutically effective amount of at least one compound, or apharmaceutically acceptable salt or solvate of the compound to a patientin need thereof, the compound being 4-[R2]-3-[R1]-1H-pyrazolo[3,4-b]pyridine, wherein R1 and R2 are each individually selected from thegroup consisting of H, alkyl, alkenyl, alkylene, alkynyl, aryl,arylalkyl, alkylaryl, arylalkenyl, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, heterocyclylalkyl, heterocyclenyl, wherein each of thealkyl, alkenyl, alkylene, alkynyl, alkynylalkyl, aryl, arylalkyl,alkylaryl, arylalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,cycloalkenylalkyl, heterocyclic moieties can be substituted with one ormore moieties which can be the same or different, each moiety beingindependently selected from the group consisting of acyl, alcohol,alkyl, aryl, aroyl, alkoxy, aryloxy, arylalkyloxy, alkylthio, arylthio,aralkylthio, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,alkylsulfonyl, arylsulfonyl, cyano, hydroxyalkyl, amide, amine, thiol,thiophene, pyrrole, furan, alkylsulfate, arylsulfate, alkylphosphate andarylphosphate.

In another aspect, the present invention provides a method of inhibitingFyn kinase in a patient, the method comprising administering atherapeutically effective amount of at least one compound, or apharmaceutically acceptable salt or solvate of the compound to a patientin need thereof, the compound being one of the4-[R2]-3-[R1]-1H-pyrazolo[3,4-b] pyridine derivatives of Tables 3 and 4.

In another aspect, the present invention provides a method of treating,or slowing progression of a disease associated with Fyn kinase, themethod comprising administering a therapeutically effective amount of atleast one compound, or a pharmaceutically acceptable salt or solvate ofthe compound to a patient in need thereof, the compound being at leastone of the 4-[R2]-3-[R1]-1H-pyrazolo[3,4-b] pyridines described above,or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, the present invention comprises methods forinhibiting Fyn kinase using N-(3-[R2] imidazo [1,2-b] pyridazin-6-yl)[R1] amine compounds or pharmaceutical compositions comprising suchcompounds and methods of treatment, prevention, inhibition oramelioration of one or more of the diseases or conditions associatedwith Fyn kinase.

In one aspect, the present invention provides a method of inhibiting Fynkinase in a patient, the method comprising administering atherapeutically effective amount of at least one compound, or apharmaceutically acceptable salt or solvate of the compound to a patientin need thereof, the compound being N-(3-[R2] imidazo [1,2-b]pyridazin-6-yl) [R1] amine, wherein R1 and R2 are each individuallyselected from the group consisting of H, alkyl, alkenyl, alkylene,alkynyl, aryl, arylalkyl, alkylaryl, arylalkenyl, cycloalkyl,cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclenyl,wherein each of the alkyl, alkenyl, alkylene, alkynyl, alkynylalkyl,aryl, arylalkyl, alkylaryl, arylalkenyl, cycloalkyl, cycloalkylalkyl,cycloalkenyl, cycloalkenylalkyl, heterocyclic moieties can besubstituted with one or more moieties which can be the same ordifferent, each moiety being independently selected from the groupconsisting of acyl, alcohol, alkyl, aryl, aroyl, alkoxy, aryloxy,arylalkyloxy, alkylthio, arylthio, aralkylthio, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, cyano,hydroxyalkyl, amide, amine, thiol, thiophene, pyrrole, furan,alkylsulfate, arylsulfate, alkylphosphate and arylphosphate.

In another aspect, the present invention provides a method of inhibitingFyn kinase in a patient, the method comprising administering atherapeutically effective amount of at least one compound, or apharmaceutically acceptable salt or solvate of the compound to a patientin need thereof, the compound being one of the N-(3-[R2] imidazo [1,2-b]pyridazin-6-yl) [R1] amine derivatives of Tables 3 and 4.

In another aspect, the present invention provides a method of treating,or slowing progression of a disease associated with Fyn kinase, themethod comprising administering a therapeutically effective amount of atleast one compound, or a pharmaceutically acceptable salt or solvate ofthe compound to a patient in need thereof, the compound being at leastone of the N-(3-[R2] imidazo [1,2-b] pyridazin-6-yl) [R1] aminedescribed above, or a pharmaceutically acceptable salt or solvatethereof.

In another aspect, the present invention provides a method of inhibitingFyn kinase in a patient, the method comprising administering atherapeutically effective amount of at least one compound, or apharmaceutically acceptable salt or solvate of the compound to a patientin need thereof, the compound selected from the group consisting ofN-[3-[6-(2-furylmethylamino)pyrazin-2-yl]phenyl]acetamide,4-[6-[1-(hydroxymethyl)propylamino]pyrazin-2-yl]phenol,2-[[6-(5-isopropyl-2-methoxy-phenyl)pyrazin-2-yl]amino]butan-1-ol,6-(3-aminophenyl)-N-benzyl-pyrazin-2-amine,2-[[6-(4-aminophenyl)pyrazin-2-yl]amino]butan-1-ol,N-[3-(dimethylamino)propyl]-3-[6-(4-methoxyphenyl)pyrazin-2-yl]benzamide,2-methoxy-4-[6-(4-methoxyphenyl)pyrazin-2-yl]phenol,N-[3-[6-(4-methoxyphenyl)pyrazin-2-yl]phenyl]acetamide,N-[3-[6-(3-hydroxyphenyl)pyrazin-2-yl]phenyl]acetamide,3-[5-(3-furylmethylamino)-3-pyridyl]phenol,N-[3-[5-(3,4,5-trimethoxyanilino)-3-pyridyl]phenyl]acetamide,3-[(3-methoxyphenyl)methyl]-5-(3,4,5-trimethoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2-one,N,N-dimethyl-3-[2-oxo-3-[(1S)-1-phenylethyl]-1H-imidazo[4,5-b]pyrazin-5-yl]benzamide,5-[3-(dimethylamino)phenyl]-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine,3-[5-[(6-methoxy-3-pyridyl)amino]pyrazolo[1,5-a]pyrimidin-3-yl]phenol,3-(3-methoxyphenyl)-N-(6-methoxy-3-pyridyl)pyrazolo[1,5-a]pyrimidin-5-amine,1-[3-[5-[(6-methoxy-3-pyridyl)amino]pyrazolo[1,5-a]pyrimidin-3-yl]phenyl]ethanone,N-[5-[[[3-(3-hydroxyphenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]-2-methyl-phenyl]methanesulfonamide,3-(3,4-dimethoxyphenyl)-N-(3-pyridylmethyl)pyrazolo[1,5-a]pyrimidin-5-amine,N-(3-pyridylmethyl)-3-(3,4,5-trimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-5-amine,N-(4-isopropylphenyl)-3-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-5-amine,3-(5-methoxy-3-pyridyl)-N-(4-morpholinophenyl)pyrazolo[1,5-a]pyrimidin-5-amine,3-(3-aminophenyl)-N-(3-pyridylmethyl)pyrazolo[1,5-a]pyrimidin-5-amine,3-(2-methoxyphenyl)-N-(3-pyridylmethyl)pyrazolo[1,5-a]pyrimidin-5-amine,(E)-3-[3-[5-(3-pyridylmethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenyl]prop-2-enoicacid,N-[3-(dimethylamino)propyl]-4-[6-(2-fluoro-3-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]benzamide,6-(1H-indol-5-yl)-N-methyl-pyrazin-2-amine,N-ethyl-2-(3,4,5-trimethoxyanilino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxamide,6-propyl-N-(3,4,5-trimethoxyphenyl)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-2-amine,[2-[3-(dimethylamino)anilino]-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl]-(2-methoxyphenyl)methanone,N-[3-(4-fluorophenyl)-6-[4-(morpholine-4-carbonyl)phenyl]imidazo[1,2-a]pyridin-8-yl]formamide,N-[3-(3-acetylphenyl)-6-[4-(morpholine-4-carbonyl)phenyl]imidazo[1,2-a]pyridin-8-yl]formamide,N-[3-(3-chloro-4-fluoro-phenyl)-6-[3-(methanesulfonamido)phenyl]imidazo[1,2-a]pyridin-8-yl]formamide,N-[3-(4-fluorophenyl)-6-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-8-yl]formamide,1-methyl-N-[4-(4-methylpiperazin-1-yl)phenyl]-2-[3-(trifluoromethyl)phenyl]pyrrolo[3,2-c]pyridin-6-amine,1-methyl-N-pyrimidin-4-yl-2-[3-(trifluoromethyl)phenyl]pyrrolo[3,2-c]pyridin-6-amine,2-(3-fluorophenyl)-1-methyl-N-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[3,2-c]pyridin-6-amine,2-(3-fluorophenyl)-1-methyl-N-pyrimidin-4-yl-pyrrolo[3,2-c]pyridin-6-amine,1-benzyl-N-[4-(4-methylpiperazin-1-yl)phenyl]-2-(3-pyridyl)pyrrolo[3,2-c]pyridin-6-amine,2-(1H-pyrazol-4-yl)-N-(2-pyridyl)-1H-pyrrolo[3,2-c]pyridin-6-amine,N-(4-methylsulfonylphenyl)-2-(1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-6-amine,1-benzyl-2-(3-pyridyl)-N-pyrimidin-4-yl-pyrrolo[3,2-c]pyridin-6-amine,N-(3-methoxyphenyl)-2-(1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-6-amine,N-(3,4-dimethoxyphenyl)-2-(1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-6-amine,1-benzyl-N-[4-(4-methylpiperazin-1-yl)phenyl]-2-phenyl-pyrrolo[3,2-c]pyridin-6-amine,N-[3-[8-acetamido-3-(3,4-dimethoxyphenyl)imidazo[1,2-a]pyridin-6-yl]phenyl]acetamide,N-[3-(3-acetylphenyl)-6-(3-methoxyphenyl)imidazo[1,2-a]pyridin-8-yl]acetamide,N-[3-(3-acetylphenyl)-6-(2,4-dimethoxyphenyl)imidazo[1,2-a]pyridin-8-yl]acetamide,N-[3-(3-acetylphenyl)-6-(2-methoxyphenyl)imidazo[1,2-a]pyridin-8-yl]acetamide,N-[6-(4-aminophenyl)-3-(4-fluorophenyl)imidazo[1,2-a]pyridin-8-yl]acetamide,N-[3-(3-acetylphenyl)-6-[4-(morpholine-4-carbonyl)phenyl]imidazo[1,2-a]pyridin-8-yl]acetamide,N,N-dimethyl-4-[4-[4-(4-methylpiperazin-1-yl)anilino]-1H-pyrrolo[3,2-c]pyridin-2-yl]benzamide,4-[2-(3,5-dimethoxyphenyl)-1H-pyrrolo[3,2-c]pyridin-4-yl]morpholine,N-[4-[[2-(2-methoxyphenyl)-1H-pyrrolo[3,2-c]pyridin-4-yl]amino]phenyl]acetamide,2-(2-methoxyphenyl)-1-methyl-N-[3-(trifluoromethyl)phenyl]pyrrolo[3,2-c]pyridin-4-amine,6-(3-chlorophenyl)-3-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-amine,5-amino-4-(1H-benzimidazol-2-yl)-1-(1,3-benzodioxol-5-yl)-2H-pyrrol-3-one,8-(2,5-dimethoxyphenyl)-7-(4-fluorophenyl)-1-methyl-3H-imidazo[1,2-g]purine-2,4-dione,methyl2-amino-1-(3-hydroxyphenyl)pyrrolo[3,2-b]quinoxaline-3-carboxylate,2-(3,4-dimethoxyphenyl)-6-hydroxy-chromen-4-one,2-amino-1-(3-methoxyphenyl)pyrrolo[3,2-b]quinoxaline-3-carboxamide.

In another aspect, the present invention provides a method of treating,or slowing progression of a disease associated with Fyn kinase, themethod comprising administering a therapeutically effective amount of atleast one compound, or a pharmaceutically acceptable salt or solvate ofthe compound to a patient in need thereof, wherein the compound isselected from the group consisting ofN-[3-[6-(2-furylmethylamino)pyrazin-2-yl]phenyl]acetamide,4-[6-[1-(hydroxymethyl)propylamino]pyrazin-2-yl]phenol,2-[[6-(5-isopropyl-2-methoxy-phenyl)pyrazin-2-yl]amino]butan-1-ol,6-(3-aminophenyl)-N-benzyl-pyrazin-2-amine,2-[[6-(4-aminophenyl)pyrazin-2-yl]amino]butan-1-ol,N-[3-(dimethylamino)propyl]-3-[6-(4-methoxyphenyl)pyrazin-2-yl]benzamide,2-methoxy-4-[6-(4-methoxyphenyl)pyrazin-2-yl]phenol,N-[3-[6-(4-methoxyphenyl)pyrazin-2-yl]phenyl]acetamide,N-[3-[6-(3-hydroxyphenyl)pyrazin-2-yl]phenyl]acetamide,3-[5-(3-furylmethylamino)-3-pyridyl]phenol,N-[3-[5-(3,4,5-trimethoxyanilino)-3-pyridyl]phenyl]acetamide,3-[(3-methoxyphenyl)methyl]-5-(3,4,5-trimethoxyphenyl)-1H-imidazo[4,5-b]pyrazin-2-one,N,N-dimethyl-3-[2-oxo-3-[(1S)-1-phenylethyl]-1H-imidazo[4,5-b]pyrazin-5-yl]benzamide,5-[3-(dimethylamino)phenyl]-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine,3-[5-[(6-methoxy-3-pyridyl)amino]pyrazolo[1,5-a]pyrimidin-3-yl]phenol,3-(3-methoxyphenyl)-N-(6-methoxy-3-pyridyl)pyrazolo[1,5-a]pyrimidin-5-amine,1-[3-[5-[(6-methoxy-3-pyridyl)amino]pyrazolo[1,5-a]pyrimidin-3-yl]phenyl]ethanone,N-[5[[3-(3-hydroxyphenyl)pyrazolo[1,5-a]pyrimidin-5-yl]amino]-2-methyl-phenyl]methanesulfonamide,3-(3,4-dimethoxyphenyl)-N-(3-pyridylmethyl)pyrazolo[1,5-a]pyrimidin-5-amine,N-(3-pyridylmethyl)-3-(3,4,5-trimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-5-amine,N-(4-isopropylphenyl)-3-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-5-amine,3-(5-methoxy-3-pyridyl)-N-(4-morpholinophenyl)pyrazolo[1,5-a]pyrimidin-5-amine,3-(3-aminophenyl)-N-(3-pyridylmethyl)pyrazolo[1,5-a]pyrimidin-5-amine,3-(2-methoxyphenyl)-N-(3-pyridylmethyl)pyrazolo[1,5-a]pyrimidin-5-amine,(E)-3-[3-[5-(3-pyridylmethylamino)pyrazolo[1,5-a]pyrimidin-3-yl]phenyl]prop-2-enoicacid,N-[3-(dimethylamino)propyl]-4-[6-(2-fluoro-3-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]benzamide,6-(1H-indol-5-yl)-N-methyl-pyrazin-2-amine,N-ethyl-2-(3,4,5-trimethoxyanilino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxamide,6-propyl-N-(3,4,5-trimethoxyphenyl)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-2-amine,[2-[3-(dimethylamino)anilino]-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl]-(2-methoxyphenyl)methanone,N-[3-(4-fluorophenyl)-6-[4-(morpholine-4-carbonyl)phenyl]imidazo[1,2-a]pyridin-8-yl]formamide,N-[3-(3-acetylphenyl)-6-[4-(morpholine-4-carbonyl)phenyl]imidazo[1,2-a]pyridin-8-yl]formamide,N-[3-(3-chloro-4-fluoro-phenyl)-6-[3-(methanesulfonamido)phenyl]imidazo[1,2-a]pyridin-8-yl]formamide,N-[3-(4-fluorophenyl)-6-(1-methylpyrazol-4-yl)imidazo[1,2-a]pyridin-8-yl]formamide,1-methyl-N-[4-(4-methylpiperazin-1-yl)phenyl]-2-[3-(trifluoromethyl)phenyl]pyrrolo[3,2-c]pyridin-6-amine,1-methyl-N-pyrimidin-4-yl-2-[3-(trifluoromethyl)phenyl]pyrrolo[3,2-c]pyridin-6-amine,2-(3-fluorophenyl)-1-methyl-N-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[3,2-c]pyridin-6-amine,2-(3-fluorophenyl)-1-methyl-N-pyrimidin-4-yl-pyrrolo[3,2-c]pyridin-6-amine,1-benzyl-N-[4-(4-methylpiperazin-1-yl)phenyl]-2-(3-pyridyl)pyrrolo[3,2-c]pyridin-6-amine,2-(I H-pyrazol-4-yl)-N-(2-pyridyl)-1H-pyrrolo[3,2-c]pyridin-6-amine,N-(4-methylsulfonylphenyl)-2-(1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-6-amine,1-benzyl-2-(3-pyridyl)-N-pyrimidin-4-yl-pyrrolo[3,2-c]pyridin-6-amine,N-(3-methoxyphenyl)-2-(1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-6-amine,N-(3,4-dimethoxyphenyl)-2-(1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-6-amine,1-benzyl-N-[4-(4-methylpiperazin-1-yl)phenyl]-2-phenyl-pyrrolo[3,2-c]pyridin-6-amine,N-[3-[8-acetamido-3-(3,4-dimethoxyphenyl)imidazo[1,2-a]pyridin-6-yl]phenyl]acetamide,N-[3-(3-acetylphenyl)-6-(3-methoxyphenyl)imidazo[1,2-a]pyridin-8-yl]acetamide,N-[3-(3-acetylphenyl)-6-(2,4-dimethoxyphenyl)imidazo[1,2-a]pyridin-8-yl]acetamide,N-[3-(3-acetylphenyl)-6-(2-methoxyphenyl)imidazo[1,2-a]pyridin-8-yl]acetamide,N-[6-(4-aminophenyl)-3-(4-fluorophenyl)imidazo[1,2-a]pyridin-8-yl]acetamide,N-[3-(3-acetylphenyl)-6-[4-(morpholine-4-carbonyl)phenyl]imidazo[1,2-a]pyridin-8-yl]acetamide,N,N-dimethyl-4-[4-[4-(4-methylpiperazin-1-yl)anilino]-1H-pyrrolo[3,2-c]pyridin-2-yl]benzamide,4-[2-(3,5-dimethoxyphenyl)-1H-pyrrolo[3,2-c]pyridin-4-yl]morpholine,N-[4-[[2-(2-methoxyphenyl)-1H-pyrrolo[3,2-c]pyridin-4-yl]amino]phenyl]acetamide,2-(2-methoxyphenyl)-1-methyl-N-[3-(trifluoromethyl)phenyl]pyrrolo[3,2-c]pyridin-4-amine,6-(3-chlorophenyl)-3-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-7-amine,5-amino-4-(IH-benzimidazol-2-yl)-1-(1,3-benzodioxol-5-yl)-2H-pyrrol-3-one,8-(2,5-dimethoxyphenyl)-7-(4-fluorophenyl)-1-methyl-3H-imidazo[1,2-g]purine-2,4-dione,methyl2-amino-1-(3-hydroxyphenyl)pyrrolo[3,2-b]quinoxaline-3-carboxylate,2-(3,4-dimethoxyphenyl)-6-hydroxy-chromen-4-one,2-amino-1-(3-methoxyphenyl)pyrrolo[3,2-b]quinoxaline-3-carboxamide.

In another aspect, the present invention provides a method of inhibitingFyn kinase in a patient, the method comprising administering atherapeutically effective amount of at least one compound, or apharmaceutically acceptable salt or solvate of the compound to a patientin need thereof, the compound being any one of those listed in Tables 3and 4.

In another aspect, the present invention provides a method of treating,or slowing progression of a disease associated with Fyn kinase, themethod comprising administering a therapeutically effective amount of atleast one compound, or a pharmaceutically acceptable salt or solvate ofthe compound to a patient in need thereof, of at least one compounddescribed above, or a pharmaceutically acceptable salt or solvatethereof. Without limitation, the Fyn kinase inhibitors described heremay be utilized to treat Types I and II diabetes, pre-diabetes and mayprove effective in facilitating overall weight control, extend longevityand improve physical and mental well-being. In addition, such Fyn kinaseinhibitors may improve exercise tolerance and increase the human body'sability to endure physical stress, as well as improve recovery fromexercise and physical stress.

Fyn kinase inhibitors may be effective cancer therapeutics and may, whenadministered prophylactically, reduce the occurrence of various cancersin an individual. Due to its central role in intracellular regulatoryphosphorylation cascades, Fyn kinase can play diverse roles in manycommon cancers. In breast cancers Fyn kinase regulates phosphorylationof ERB receptors and has been directly implicated in the genesis oftamoxifen and trastuzumab resistant breast cancers. Fyn kinase is alsoimplicated in many forms of prostate cancer and Fyn expression isunusually high in prostate cancer cells. In liver cancers, andhepatocellular cancers generally, Fyn expression also appears to besignificantly elevated. Mutant pancreatic cancer cells transfected withhighly expressed kinase-dead Fyn genes have been shown to have decreasedliver metastases activity in mouse models, suggesting a model by whichFyn kinase activity regulates cell proliferation and apoptosis.Esophageal and gastric cancers also exhibit high levels of Fyn kinaseand such cancers are thought to be particularly sensitive to theepidermal growth factor receptor signaling pathway in which Fyn plays akey role. Fyn also plays a role in cervical and ovarian cancers.Elevated levels of Fyn kinase observed in many such cancers appears tobe the result of overexpression of NRDG1, which when suppressed by shRNAtreatment results in concomitant decrease in Fyn expression and asubsequent decrease in cell adhesion, migration and invasion activity.

Existing Fyn kinase inhibitors are also known to mitigate and lessen theseverity of neurodegenerative diseases such as Multiple Sclerosis,Alzheimer's and Parkinson's and the Fyn kinase inhibitors described heremay exhibit improved therapeutic efficacy in such treatments. The Fynkinase inhibitors described here may also be effective in improvingrecovery from head or spinal trauma as well as promoting overallneurological health.

The invention described here relate to pharmacophores identified byanalysis of specific chemical, physical and biological properties of alarge set of chemical combinations based on a limited set ofpharmacores. Such pharmacophores define the relevant parametersnecessary to specifically modulate Fyn kinase activity and to providetherapeutic treatment for physiologic and pathologic conditions amenableto treatment by regulation of Fyn kinase activity in patients in need ofsuch treatment.

Definitions

As used herein and throughout this disclosure, the following terms areto be understood to have the following meaning.

“Acyl” means an H—C(O)—, alkyl-C(O)— or cycloalkyl-C(O)—, group in whichthe various groups are as previously described. The bond to the parentmoiety is through the carbonyl. Preferred acyls contain a lower alkyl.Non-limiting examples of suitable acyl groups include formyl, acetyl andpropanoyl.

“Alcohol” means a functional group of the general formula R—OH, whereinR represents and alkane, alkene or any other carbon-containing group.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain about 1 to about 12 carbon atoms in thechain. More preferred alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more lower alkyl groupssuch as methyl, ethyl or propyl, are attached to a linear alkyl chain.“Lower alkyl” means a group having about 1 to about 6 carbon atoms inthe chain which may be straight or branched. “Alkyl” may beunsubstituted or optionally substituted by one or more substituentswhich may be the same or different, each substituent being independentlyselected from the group consisting of halo, alkyl, aryl, cycloalkyl,cyano, hydroxy, alkoxy, alkylthio, amino, —NH(alkyl), —NH(cycloalkyl),—N(alkyl)2, carboxy and —C(O)O-alkyl. Non-limiting examples of suitablealkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.

“Alkenyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkenyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 6 carbon atoms in the chain. Branchedmeans that one or more 20 lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkenyl chain. “Lower alkenyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. “Alkenyl” may be unsubstituted or optionally substituted byone or more substituents which may be the same or different, eachsubstituent being independently selected from the group consisting ofhalo, alkyl, aryl, cycloalkyl, cyano, alkoxy and -5(alkyl). Non-limitingexamples of suitable alkenyl groups include ethenyl, propenyl,n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

“Alkoxy” means an alkyl-O-group. Non-limiting examples of suitablealkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy andn-butoxy. The bond to the parent moiety is through the ether oxygen.

“Alkylene” means a difunctional group obtained by removal of a hydrogenatom from an alkyl group that is defined above. Non-limiting examples ofalkylene include methylene, ethylene and propylene.

“Alkynyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkynyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 4 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkynyl chain. “Lower alkynyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkynyl groups includeethynyl, propynyl, 2-butynyl and 3-methylbutynyl. “Alkynyl” may beunsubstituted or optionally substituted by one or more substituentswhich may be the same or different, each substituent being independentlyselected from the group consisting of alkyl, aryl and cycloalkyl.

“Alkynylalkyl” means an alkynyl-alkyl- group in which the alkynyl andalkyl are as previously described. Preferred alkynylalkyls contain alower alkynyl and a lower alkyl group. The bond to the parent moiety isthrough the alkyl. Non-limiting examples of suitable alkynylalkyl groupsinclude propargylmethyl.

“Alkylphosphate” means a compound of the general formula ROP(O)3-,wherein the R represents any alkyl group.

“Alkylsulfate” means a compound of the general formula ROS(O)3-, whereinthe R represents any alkyl group.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. The aryl group can be optionally substituted with oneor more “ring system substituents” which may be the same or different,and are as defined herein. Non-limiting examples of suitable aryl groupsinclude phenyl and naphthyl.

“Aroyl” means an aryl-C(O)-group. The bond to the parent moiety isthrough the carbonyl. Non-limiting examples of suitable groups includebenzoyl and 1-naphthoyl.

“Arylalkyl” means an aryl-alkyl- group in which the aryl and alkyl areas previously described. Preferred aralkyls comprise a lower alkylgroup. Non-limiting examples of suitable aralkyl groups include benzyl,2-phenethyl and naphthalenylmethyl. The bond to the parent moiety isthrough the alkyl.

“Alkylaryl” means an alkyl-aryl-group in which the alkyl and aryl are aspreviously described. Preferred alkylaryls comprise a lower alkyl group.A non-limiting example of a suitable alkylaryl group is tolyl. The bondto the parent moiety is through the aryl.

“Alkylthio” means an alkyl-S-group. Non-limiting examples of suitablealkylthio groups include methylthio and ethylthio. The bond to theparent moiety is through the sulfur.

“Arylphosphate” means a compound of the general formula ROP(O)3-,wherein the R represents any aryl group.

“Arylsulfate” means a compound of the general formula ROS(O)3-, whereinthe R represents any aryl group.

“Arylthio” means an aryl-S-group. Non-limiting examples of suitablearylthio groups include phenylthio and naphthylthio. The bond to theparent moiety is through the sulfur.

“Alkoxycarbonyl” means an alkyl-O—CO-group. Non-limiting examples ofsuitable alkoxycarbonyl groups include methoxycarbonyl andethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

“Aryloxycarbonyl” means an aryl-O—C(O)-group. Non-limiting examples ofsuitable aryloxycarbonyl groups include phenoxycarbonyl andnaphthoxycarbonyl. The bond to the parent moiety is through thecarbonyl.

“Aralkoxycarbonyl” means an aralkyl-O—C(O)— group. Non-limiting exampleof a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond tothe parent moiety is through the carbonyl.

“Alkylsulfonyl” means an alkyl-S(02)-group. Preferred groups are thosein which the alkyl group is lower alkyl. The bond to the parent moietyis through the sulfonyl.

“Amide” means a functional group comprising (R1)C(O)N(R2)(R3) whereinthe R groups refer to H or organic groups and the carbon and nitrogenatoms are covalently linked. Other amides include “sulfonamides” of thegeneral formula (R1)S(O2)N(R2)(R3), wherein the sulfur and nitrogenatoms are covalently linked; and “phosphoramides” of the general formula(R1)(R2)O(O)N(R3)(R4), wherein the phosphate and the nitrogen arecovalently linked. A non-limiting example of an amide is acetamide.

“Amine” means a functional group comprising: NI-12(R1), a “primaryamine”; NH(R1)(R2), a “secondary amine”: N(R1)(R2)(R3), a “tertiaryamine”, wherein the bond to the parent moiety runs through the nitrogen.

“Arylsulfonyl” means an aryl-S(02)-group. The bond to the parent moietyis through the sulfonyl.

“Aralkylthio” means an aralkyl-S-group in which the aralkyl group is aspreviously described. Non-limiting example of a suitable aralkylthiogroup is benzylthio. The bond to the parent moiety is through thesulfur.

“Arylalkenyl” means an alkenyl-aryl-group. Preferred arylalkenylscomprise a lower alkenyl group. A non-limiting example of a suitablearylalkenyl group is phenylacetylene.

“Aryloxy” means an aryl-O-group. Non-limiting examples of suitablearyloxy groups include phenoxy and naphthoxy. The bond to the parentmoiety is through the ether oxygen.

“Aralkyloxy” means an aralkyl-O-group in which the aralkyl group is aspreviously described. Non-limiting examples of suitable aralkyloxygroups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to theparent moiety is through the ether oxygen.

“Composition” is intended to encompass a product comprising thespecified ingredients in the specified amounts, as well as any productwhich results, directly or indirectly, from combination of the specifiedingredients in the specified amounts.

“Cyano” means a —CN group in which the bond to the parent moiety isthrough the carbon.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl can be optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined above. Non-limiting examples of suitable monocycliccycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and the like. Non-limiting examples of suitable multicycliccycloalkyls include 1-decalinyl, norbomyl, adamantyl and the like.

“Cycloalkylalkyl” means a cycloalkyl moiety as defined above linked viaan alkyl moiety (defined above) to a parent core. Non-limiting examplesof suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyland the like.

“Cycloalkenyl” means a non-aromatic mono or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms which contain at least one carbon-carbon double bond.Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. Thecycloalkenyl can be optionally substituted with one or more “ring systemsubstituents” which may be the same or different, and are as definedabove. Non-limiting examples of suitable monocyclic cycloalkenylsinclude cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl, and thelike. Non-limiting example of a suitable multicyclic cycloalkenyl isnorbomylenyl.

“Cycloalkenylalkyl” means a cycloalkenyl moiety as defined above linkedvia an alkyl moiety (defined above) to a parent core. Non-limitingexamples of suitable cycloalkenylalkyls include cyclopentenylmethyl,cyclohexenylmethyl and the like.

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the present inventioneffective in inhibiting the above-noted diseases and thus producing thedesired therapeutic, ameliorative, inhibitory or preventative effect.

“Furan” is a heterocyclic aromatic compound of the formula C4H4O.Compounds comprising such structures may be referred to as “furans.”

“Halogen” or “halo” means fluorine, chlorine, bromine, or iodine.Preferred are fluorine, chlorine and bromine.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one or more of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination. Preferred heteroaryls contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted by one or more“ring system substituents” which may be the same or different, and areas defined herein. The prefix aza, oxa or thia before the heteroarylroot name means that at least one of a nitrogen, oxygen or sulfur atomrespectively, is present as a ring atom. A nitrogen atom of a heteroarylcan be optionally oxidized to the corresponding N-oxide. Non-limitingexamples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl,thienyl, pyrimidinyl, pyridone (including N-substituted pyridones),isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl,pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl,pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl,imidazo[1,2-a]pyridinyl, imidazo[2, 1-b]thiazolyl, benzofurazanyl,indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl,imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like. The term “heteroaryl” alsorefers to partially saturated heteroaryl moieties such as, for example,tetrahydroisoquinolyl, tetrahydroquinolyl and the like.

“Heteroarylalkyl” means a heteroaryl moiety as defined above linked viaan alkyl moiety (defined above) to a parent core. Non-limiting examplesof suitable heteroarylalkyls include 2-pyridinylmethyl, quinolinylmethyland the like.

“Heterocyclyl” means a non-aromatic saturated monocyclic or multicyclicring system comprising about 3 to about 10 ring atoms, preferably about5 to 30 about 1 0 ring atoms, in which one or more of the atoms in thering system is an element other than carbon, for example nitrogen,oxygen or sulfur, alone or in combination. There are no adjacent oxygenand/or sulfur atoms present in the ring system. Preferred heterocyclylscontain about 5 to about 6 ring atoms. The prefix aza, oxa or thiabefore the heterocyclyl root name means that at least a nitrogen, oxygenor sulfur atom respectively is present as a ring atom. Any —NH in aheterocyclyl ring may exist protected such as, for example, as an—N(Boc), —N(CBz), —N(Tos) group and the like; such protections are alsoconsidered part of this invention. The heterocyclyl can be optionallysubstituted by one or more “ring system substituents” which may be thesame or different, and are as defined herein. The nitrogen or sulfuratom of the heterocyclyl can be optionally oxidized to the correspondingN-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitablemonocyclic heterocyclyl rings include piperidyl, pyrrolidinyl,piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl,tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like.

“Heterocyclylalkyl” means a heterocyclyl moiety as defined above linkedvia an alkyl moiety (defined above) to a parent core. Non-limitingexamples of suitable heterocyclylalkyls include piperidinylmethyl,piperazinylmethyl and the like.

“Heterocyclenyl” means a non-aromatic monocyclic or multicyclic ringsystem comprising about 3 to about 1 0 ring atoms, preferably about 5 toabout 10 ring atoms, in which one or more of the atoms in the ringsystem is an element other than carbon, for example nitrogen, oxygen orsulfur atom, alone or in combination, and which contains at least onecarbon-carbon double bond or carbon-nitrogen double bond. There are noadjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms.The prefix aza, oxa or thia before the heterocyclenyl root name meansthat at least a nitrogen, oxygen or sulfur atom respectively is presentas a ring atom. The heterocyclenyl can be optionally substituted by oneor more ring system substituents, wherein “ring system substituent” isas defined above. The nitrogen or sulfur atom of the heterocyclenyl canbe optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable heterocyclenyl groupsinclude 1,2,3,4-tetrahydropyridine, 1,2-dihydropyridyl,1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine,1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl,2-imidazolinyl, 2-pyrazolinyl, dihydroimidazole, dihydrooxazole,dihydrooxadiazole, dihydrothiazole, 3,4-dihydro-2H-pyran,dihydrofuranyl, fluorodihydrofuranyl, 7oxabicyclo[2.2.1]heptenyl,dihydrothiophenyl, dihydrothiopyranyl, and the like.

“Hydroxyalkyl” means a HO-alkyl- group in which alkyl is as previouslydefined.

Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples ofsuitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

“Patient” or “Subject” includes both human and animals.

“Pharmacore” means a specific chemical structure to which combinationsof additional chemical constituents may be added. The combination ofpharmacore and additional chemical groups represents the“pharmacophore.”

“Pharmacophore” is the ensemble of steric and electronic features of apharmacore and any additional chemical constituents necessary to ensuresupramolecular interactions with a specific biological target structureto trigger or block its biological response. A pharmacophore does notnecessarily represent a real molecule or association of functionalgroups, although it may, but embodies the concept that accounts for thecommon molecular interaction capacities of a group of compounds towardstheir target structure. The pharmacophore can be considered the largestcommon denominator shared by a set of active molecules.

“Physiologic function” is the physiological activity of an organ, bodypart, or pathway within an animal.

“Purified”, “in purified form”, “isolated”, or “in isolated and purifiedform” for a compound refers to the physical state of said compound afterbeing isolated from a synthetic process or natural source or combinationthereof. Thus, the term “purified”, “in purified form”, “isolated”, or“in isolated and purified form” for a compound refers to the physicalstate of said compound after being obtained from a purification processor processes described herein or well known to the skilled artisan, insufficient purity to be characterizable by standard analyticaltechniques described herein or well known to the skilled artisan.

“Pyrrole” is a heterocyclic aromatic compound of the formula C4H4N.Compounds comprising such structures may be referred to as “pyrroles.”

“Ring system substituent” means a substituent attached to an aromatic ornon-aromatic ring system which, for example, replaces an availablehydrogen on the ring system. Ring system substituents may be the same ordifferent, each being independently selected from the group consistingof alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl,heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl,hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo,nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio,cycloalkyl, heterocyclyl, —C(═N—CN)—NH2, —C(═NH)—NH2, —C(═NH)—NH(alkyl),Y1 Y2N-, Y1Y2N-alkyl-, Y1Y2NC(O)—, Y1Y2NSOr and —S02NY1Y2, wherein Y1and Y2 can be the same or different and are independently selected fromthe group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl.“Ring system substituent” may also mean a single moiety whichsimultaneously replaces two available hydrogens on two adjacent carbonatoms (one H on each carbon) on a ring system. Examples of such moietiesare methylene dioxy, ethylenedioxy, —C(CH3) 2- and the like.

“Substituted” means that one or more hydrogens on the designated atom isreplaced with a selection from the indicated group, provided that thedesignated atom's normal valency under the existing circumstances is notexceeded, and that the substitution results in a stable compound.Combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds. By “stable compound’ or“stable structure” is meant a compound that is sufficiently robust tosurvive isolation to a useful degree of purity from a reaction mixture,and formulation into an efficacious therapeutic agent. The term“optionally substituted” means optional substitution with the specifiedgroups, radicals or moieties.

“Thiol” means a functional group of the general formula R—SH, wherein Rrepresents and alkane, alkene or any other carbon-containing group, mayalso be referred to as a “mercaptan” or “sulfhydryl” group.

“Thiophene” is a heterocyclic aromatic compound of the formula C4H4S,may also be referred to as thiofuran.

Any carbon as well as heteroatom with unsatisfied valences in the text,examples and Tables herein is assumed to have the sufficient number ofhydrogen atom(s) to satisfy the valences.

The compounds described herein may contain asymmetric or chiral centers,and, therefore, exist in different stereoisomeric forms. It is intendedthat all stereoisomeric forms of these compounds as well as mixturesthereof, including racemic mixtures, form part of the present invention.In addition, the present invention embraces all geometric and positionalisomers. For example, if a compound incorporates a double bond or afused ring, both the cis- and trans-forms, as well as mixtures, areembraced within the scope of the invention.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers.Enantiomers can also be separated by use of chiral HPLC column.

The compounds herein may in some cases form salts which are also withinthe scope of this invention. Reference to a compound herein isunderstood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases.

“Solvate” means a physical association of a compound of this inventionwith one or more solvent molecules. This physical association involvesvarying degrees of ionic and covalent bonding, including hydrogenbonding. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.“Hydrate” is a solvate wherein the solvent molecule is water. One ormore compounds of the invention may also exist as, or optionally beconverted to, a solvate. Preparation of solvates is generally known.

The compounds of this invention may exist in unsolvated as well assolvated forms with pharmaceutically acceptable solvents such as water,ethanol, and the like, and it is intended that the invention embraceboth solvated and unsolvated forms.

It is also possible that the compounds herein may exist in differenttautomeric forms, and all such forms are embraced within the scope ofthe invention, for example, all keto-enol and imine-enamine forms of thecompounds are included in the invention.

DETAILED DESCRIPTION OF THE INVENTION

Identifying FYN Kinase Inhibitors.

Individual compounds within a chemical library consisting of 600potential kinase inhibitors were assayed with the ADP-Glo™ Kinase Assaykit (V9102, Promega UK Ltd. Southhampton, Hampshire, UK) to identify themost potent FYN kinase inhibitors within the collection. The chemicallibrary was comprised of the SoftFocus ATP-competitive hinge bindingcompounds described by Harris, C. J., Hill, R. D., Sheppard, D. W., etal., The Design and Application of Target-Focused Compound Libraries.Combinatorial Chemistry and High Throughput Screening 14:521-31 (2011).The specific pharmacore chemistries included SFK52 comprising6-[R2]-3-[R1]imidazo[1,2-b] pyridazine compounds, SFK33 comprisingN-(3-[R2] imidazo [1,2-b] pyridazin-6-yl) [R1] amine compounds, SFK49comprising N-(5-[R2] imidazo [2,1-b][1,3,4] thiadiazol-2-yl)[R1]-aminecompounds, SFK 40 comprising 5-[R2]-3-[R1] pyridin-2-amine compounds,SFK43 comprising 6-[R2]-3-[R1]imidazo[1,2-a]pyrazine compounds, andSFK63. The scaffold structure of each pharmacore is shown in Table 2.The chemical structures of the initial 600 potential kinase inhibitorsare presented in Table 3, with those chosen for additional analysispresented in Table 4. Comparison of the compounds presented in Table 1and those of Tables 2, 3 and 4, illustrate the novelty of the chemicalstructures claimed herein.

FYN kinase (10 micrograms) was from the FYN A Kinase Enzyme System(V3571, Promega UK Ltd.), a full-length recombinant human FYN Acontaining an N-terminal GST tag of about 85 kDa, expressed bybacullovirus in S19 insect cells, supplied at a concentration of 0.1microgram/microliter in 5×reaction buffer. The FYN substrate, a 12 aminoacid peptide of the sequence EFGTYGTLSKKK, containing a single tyrosinephosphorylation site, was custom synthesized (Peptide Synthetics,Peptide Protein Research, Fareham, UK) and supplied as a 4 mg/ml aqueoussolution. All other reagents were obtained from Sigma (Sigma-Aldrich,Gillingham, Dorset, UK), with the exception of UltraPure ATP (V9102,Promega UK Ltd.) and the ATP-competitive broad spectrum protein kinaseinhibitor staurosporine (569397, Merck Millipore, Watford,Hertfordshire, UK), or as otherwise indicated.

The assay procedure determines the IC50 of each potential FYN kinaseinhibitor by measuring the enzyme catalyzed ATP-dependentphosphorylation of the FYN substrate peptide. The ADP-Glo™ Kinase Assayis specifically designed to quantify kinase activity by measuring theADP produced in the reaction The reaction buffer comprises 40 mMTris.HCl (pH 7.5), 20 mM MgCl₂, 0.1 mg/ml BSA and 5 microM DTT.Individual compounds within the chemical library were dissolved in DMSOat known concentrations. Briefly, 2.5 microliters of reaction buffercontaining 3 picograms of FYN kinase and serial dilutions of eachpotential FYN kinase inhibitor (9 3-fold dilutions of a 10 micromolartop sample) are placed into each well of a 384 well microtiter plate andincubated at room temperature for 30 minutes. An additional 2.5microliters of reaction buffer containing 100 picograms of the FYNsubstrate and 12.5 picomoles of ATP are then added to each well and thereaction carried out for 90 minutes at room temperature. The reactionsare terminated by addition of 5 microliters of the ADP-Glo™ Reagentcomponent of the ADP-Glo™ Kinase Assay kit to each well. The ADP-Glo™Reagent comprises an ATP-dependent adenylate cyclase, an inorganicpyrophosphatase and an excess of staurosporine. The adenylate cyclaseconverts the remaining ATP to cAMP and pyrophospahte, thepyrophosphatase converts the pyrophosphate to phosphate and thestaurosporine inhibits the activity of the FYN kinase, the net effect isto remove all residual ATP while preserving the ADP produced by FYNkinase. The terminated reactions are incubated for 40 minutes at roomtemperature, prior to addition of the Kinase Detection Reagent componentof the ADP-Glo™ Kinase Assay kit to each well. The Kinase DetectionReagent comprises pyruvate kinase, phosphoenol pyruvate (PEP), luciferinand luciferase. The pyruvate kinase converts PEP to pyruvate and in theprocess generates ATP from the residual ADP present in the terminatedreaction. The ATP is then consumed by the luciferase catalyzed, lightemitting conversion of luciferin to oxyluciferin producing AMP,pyrophosphate and CO2. The emitted light was measured on an EnvionLuminometer to determine the relative activity of the FYN kinase in eachwell. A 10 point dose-response curve for each potential FYN kinaseinhibitor dilution series was used to determine the IC50, of eachcompound. Details of the analysis, including assay procedures andrepresentative dilution schema for measuring kinase inhibitors arepresented in the Technical Manual accompanying the ADP-GIo™ Kinase Assaykit (Doc. TM313. Promega Corp.) as well as U.S. Pat. Nos. 8,183,007 and8,802,411, the contents of which are incorporated herein, in theirentirety.

The results of screening candidate libraries are presented in Table 3,which lists the structure of each compound, the standard IUPAC name ofthe compound, the observed IC50 and the calculated lipophilicity of thecompound. The most potent FYN kinase inhibitors, generally those withthe most favorable combination of IC50 and drugability wereresynthesized and subjected to further testing and expansion. Ingeneral, the best candidate compounds exhibit an IC50 of less than 200nM and and drugability as measured by LLE (Ligand-lipophilicityefficiency) of greater than 2.5. LLE=(pIC50-c Log P) where pIC50 is thenegative log of the observed IC50 and c Log P is a calculated consensusmeasure of the lipophilicity of the compound. In practice, this means ac Log P of less than 3.5, based on an average IC50 of less than or equalto 1 μM, represents a favorable level of drugability (LLE>2.5).Candidate compounds selected for additional testing and expansion arelisted in Table 4.

Cell Based Assay(s) of FYN Kinase Inhibitors

Test compounds exhibiting superior IC50 and LLE profiles are furthertested for their ability to stimulate T cell proliferation and toinhibit production of Interleukin 2 by stimulated T-cells.

T-cell proliferation is analyzed by staining with carboxy-fluoresceindiacetate succinimidyl ester (CFSE) at a final concentration 5 μM(Molecular Probes, Invitrogen) according to the manufacturer'sinstructions. Briefly, cells are resuspended in warm PBS containing 5 μMCFSE and incubated at 37° C. for 10 minutes. Subsequently, cells arewashed twice and resuspended in culture media containing 10% FBS beforethe experimental treatments are initiated. Cells may be analyzed by flowcytometry after 5 days in culture. Alternatively, a 96-well plate iscoated with a monoclonal antibody to CD3 (G19-4), the antibody isallowed to bind, and then the plate is washed. Normal human peripheralblood T cells are added to the wells, along with test compound andanti-CD28 antibody to provide co-stimulation. After 3 days,[³H]thymidine is added to the cells and incubated for 6 hours. The cellsare harvested and counted in a liquid scintillation counter to measureproliferation.

To measure the ability of test compounds to block IL-2 production by Fynmediated tyrosine phosphorylation induced by anti-CD3 and IL-2stimulated T-cell proliferation, human T-cells, such as Jurkat cells arepreincubated with various concentrations of test compound in serum-freemedium at 37° C. for 10 min and then stimulated with plastic-immobilizedanti-CD3 mAbs. Cells are cultured in complete media supplemented with 5%fetal bovine serum for 24 h in the presence of 10 μg/ml of anti-humanCD25 mAbs to prevent IL-2 autocrine consumption. The supernatants arethen harvested and centrifuged, and the IL-2 in the supernatant measuredin a bioassay using a murine IL-2-dependent cell line, such as CTLL-4,as described by Trevillyan, et al., J. Immunol. 145:3223-30 (1990). Toavoid the influence of residual test compound in the supernatants onproliferation of CTLL-4 cells, the test compound is removed by extensivedialysis against phosphate-buffered saline (0.1 M, pH 7.4). A controlsupernatant harvested from anti-CD3-stimulated Jurkat cells lacking Lckis spiked with 200 EM test compound is included along with the testcompound dilution series to ascertain that all test compound is removedby the dialysis procedure. This “dialysis control” supernatantstimulates CTLL-4 proliferation as well as the positive controlsupernatant without added test compound, indicating the dialysisprocedure has removed the test compound. Alternatively, IL-2 can bedirectly measured with an in vitro cytokine assays using labeledanti-IL2 mAbs, such as CisBio's Human IL2 Assay Kit (CisBio US. Bedford.Mass.) without requiring prior removal of test compound.

One of skill in the art will recognize that other assays may be devisedto measure the efficacy of Fyn kinase inhibition by test compounds andthat such assays are conventional in the art and known to those ofordinary skill.

TABLE 2 Representative scaffold structures of SoftFocus librarypharmacores

5-[R2]-3-[R1]pyridin-2-amine Formula I (SFK40 pharmacore)

6-[R2]-3-[R1]imidazo[1,2-a] pyrazine Formula II (SFK43 pharmacore)

6-[R2]-3-[R1]imidazo[1,2-b] pyridazine Formula III (SFK52 pharmacore)

N-(5-[R2]imidazo[2,1- b][1,3,4]thiadiazol-2- yl)[R1]amine Formula IV(SFK49 pharmacore)

4-[R2]-3-[R1]-1H- pyrazolo[3,4-b]pyridine Formula V (SFK63 pharmacore)

N-(3-[R2]imidazo[1,2- b]pyridazin-6-yl)[R1]amine Formula VI (SFK33pharmacore)

TABLE 3 Primary screen- initial compounds. logP IC50 (con- FYN sen-Structure IUPAC name (μM) sus) Compound ID.

1 N-[3-[6-(2-furyl- methylamino) pyrazin-2- yl]phenyl] acetamide11.18502 1.66 035_0144_0081

2 4-[6-[1- (hydroxymethyl) propylamino] pyrazin-2- yl]phenol 15.345911.58 035_0153_0080

3 2-[[6-(5-isopropyl- 2-methoxy- phenyl)pyrazin-2- yl]amino]butan- 1-ol11.79042 2.97 035_0153_0286

4 6-(3- aminophenyl)-N- benzyl-pyrazin-2- amine 6.67663 2.53035_0232_0005

5 2-[[6-(4- aminophenyl) pyrazin-2- yl]amino]butan- 1-ol 21.05663 1.06035_0153_0333

6 3-[5-(3-furyl- methylamino)- 3-pyridyl]phenol 10.89609 2.44081_0284_2069

7 N-[3-[5-(3,4,5- trimethoxyanilino)- 3-pyridyl]phenyl] acetamide 0.39132.61 081_0087_0081

8 3-[(3- methoxyphenyl) methyl]-5-(3,4,5- trimethoxy- phenyl)-1H-imidazo[4,5- b]pyrazin-2-one 23.44 3.07 170_4313_0087

9 N,N-dimethyl-3- [2-oxo-3-[(1S)-1- phenylethyl]-1H- imidazo[4,5-b]pyrazin-5- yl]benzamide 1.77669 3.42 170_0148_0349

10 5-[3-(dimethyl- amino)phenyl]- N-(4-morpholino- phenyl) imidazo[1,2-a]pyrazin-8- amine 2.70242 3.14 184_0088_0135

11 N-(2-methoxy- ethyl)-3-(3- thienyl)imidazo [1,2-b]pyridazin- 6-amine5.2312 2.02 229_0033_0074

12 3-(3,4- dimethoxy- phenyl)-N-(2- methoxyethyl) imidazo[1,2-b]pyridazin-6- amine 1.54534 1.93 229_0033_0079

13 3-(4-fluoro- phenyl)-N-(2- methoxyethyl) imidazo[1,2- b]pyridazin-6-amine 4.00393 2.38 229_0033_0339

14 4-[6-(2- furylmethyl- amino) imidazo[1,2- b]pyridazin-3- yl]benzoicacid 3.879 2.73 229_0144_0140

15 N-(2-furyl- methyl)-3-(4- methoxyphenyl) imidazo[1,2- b]pyridazin-6-amine 3.67644 2.91 229_0144_0280

16 [4-[6-(2-furyl- methylamino) imidazo[1,2- b]pyridazin-3- yl]phenyl]methanol 2.20497 2.30 229_0144_0285

17 [3-[6-(2-furyl- methylamino) imidazo[1,2- b]pyridazin-3- yl]phenyl]methanol 3.85557 2.30 229_0144_0291

18 1-[3-[6-(2-furyl- methylamino) imidazo[1,2- b]pyridazin-3- yl]phenyl]ethanone 0.99711 2.63 229_0144_4145

19 [4-[6-(2- thienylmethyl- amino) imidazo[1,2- b]pyridazin-3-yl]phenyl] methanol 1.09479 3.16 229_0146_0285

20 3-(4-amino- phenyl)-N-(2- thienylmethyl) imidazo[1,2- b]pyridazin-6-amine 5.42153 3.10 229_0146_0333

21 3-(4-fluoro- phenyl)-N-(2- thienylmethyl) imidazo[1,2- b]pyridazin-6-amine 3.28447 4.07 229_0146_0339

22 3-(3- methoxyphenyl)- N-(2- thienylmethyl) imidazo[1,2-b]pyridazin-6- amine 2.94644 3.77 229_0146_4140

23 1-[3-[6-(2- thienylmethyl- amino) imidazo[1,2- b]pyridazin-3-yl]phenyl] ethanone 0.44073 3.48 229_0146_4145

24 2-[[3-(3,4,5- trimethoxy- phenyl) imidazo[1,2- b]pyridazin-6-yl]amino] butan-1-ol 1.2806 2.06 229_0153_0087

25 2-[[3-(4- methoxyphenyl) imidazo[1,2- b]pyridazin-6- yl]amino]butan-1-ol 1.27502 2.38 229_0153_0280

26 2-[[3-[4- (hydroxy- methyl)phenyl] imidazo[1,2- b]pyridazin-6-yl]amino]butan- 1-ol 2.46631 1.77 229_0153_0285

27 2-[[3-(6- methoxy-3- pyridyl)imidazo [1,2-b]pyridazin- 6-yl]amino]butan-1-ol 2.36648 1.76 229_0153_0311

28 2-[[3-(3- methoxyphenyl) imidazo[1,2- b]pyridazin-6- yl]amino]butan-1-ol 1.55019 1.76 229_0153_4140

29 [3-[6-[(3- chlorophenyl) methylamino] imidazo[1,2- b]pyridazin-3-yl]phenyl] methanol 5.10524 3.85 229_0223_0291

30 3-(4- aminophenyl)- N-[(3- chlorophenyl) methyl]imidazo[1,2-b]pyridazin- 6-amine 3.41043 3.79 229_0223_0333

31 [4-[6-[(4- fluorophenyl) methylamino] imidazo[1,2- b]pyridazin-3-yl]phenyl] methanol 2.4449 3.39 229_0224_0285

32 N-(1,3- benzodioxol-5- ylmethyl)-3-(4- pyridyl)imidazo[1,2-b]pyridazin- 6-amine 0.37966 2.42 229_0236_0069

33 4-[6-(1,3- benzodioxol- 5-ylmethyl- amino) imidazo[1,2-b]pyridazin-3- yl]phenol 5.67256 3.33 229_0236_0080

34 3-(benzofuran- 2-yl)-N-(4- pyridylmethyl) imidazo[1,2- b]pyridazin-6-amine 6.44995 2.87 229_0237_0073

35 3-(3- aminophenyl)- N-tetrahydro- pyran-4-yl- imidazo[1,2-b]pyridazin-6- amine 0.74599 1.42 229_0242_0005

36 3-(3,4- dimethoxy- phenyl)-N-tetra- hydropyran-4- yl-imidazo[1,2-b]pyridazin-6- amine 0.54713 1.93 229_0242_0079

37 N-[3-[6- (tetrahydro- pyran-4- ylamino) imidazo[1,2- b]pyridazin-3-yl]phenyl] acetamide 0.58811 1.49 229_0242_0081

38 N- tetrahydropyran- 4-yl-3-(3,4,5- trimethoxy- phenyl) imidazo[1,2-b]pyridazin-6- amine 0.61737 1.78 229_0242_0087

39 3-(1H-indol- 5-yl)-N- tetrahydropyran- 4-yl-imidazo[1,2-b]pyridazin-6- amine 1.16563 2.35 229_0242_0204

40 3-(3-methoxy- phenyl)-N- tetrahydro- pyran-4- yl-imidazo[l,2-b]pyridazin-6- amine 0.87042 2.09 229_0242_4140

41 2-methoxy- 4-[6-[(4- methoxyphenyl) methylamino] imidazo[1,2-b]pyridazin-3- yl]phenol 4.01326 3.39 229_0244_0314

42 3-[[3-(1,3- benzodioxol-5- yl)imidazo[1,2- b]pyridazin-6- yl]amino]propan-1-ol 0.9286 1.28 229_0248_0068

43 3-[[3-(1H- indol-5- yl)imidazo[1,2- b]pyridazin-6- yl]amino]propan-1-ol 2.71742 1.76 229_0248_0204

44 3-[[3-[3- (trifluoro- methyl)phenyl] imidazo[1,2- b]pyridazin-6-yl]amino] propan-1-ol 3.41334 2.54 229_0248_0312

45 4-[6-(3- hydroxy- propylamino) imidazo[1,2- b]pyridazin- 3-yl]-2-methoxy- phenol 0.32856 1.20 229_0248_0314

46 3-[[3-(4- phenoxyphenyl) imidazo[1,2- b]pyridazin-6- yl]amino]propan-1-ol 5.54336 3.16 229_0248_1029

47 (2S)-2-[[3-(3- aminophenyl) imidazo[1,2- b]pyridazin-6- yl]amino]-3-methyl-butan- 1-ol 1.80698 2.07 229_0254_0005

48 (2S)-2-[[3-(1,3- benzodioxol-5- yl)imidazo[1,2- b]pyridazin-6-yl]amino]-3- methyl-butan- 1-ol 1.82017 2.52 229_0254_0068

49 (2S)-2-[[3-(3,4- dimethoxyphenyl) imidazo[1,2- b]pyridazin-6-yl]amino]-3- methyl-butan- 1-ol 0.7782 2.59 229_0254_0079

50 N-[3-[6-[[(1S)-1- (hydroxymethyl)- 2-methyl- propyl]amino]imidazo[1,2- b]pyridazin-3- yl]phenyl] acetamide 0.80076 2.14229_0254_0081

51 4-[6-[[(1S)-1- (hydroxymethyl)- 2-methyl- propyl]amino] imidazo[1,2-b]pyridazin-3- yl]benzonitrile 3.17911 2.76 229_0254_0086

52 (2S)-2-[[3-(4- aminophenyl) imidazo[1,2- b]pyridazin-6- yl]amino]-3-methyl-butan- 1-ol 3.05172 2.07 229_0254_0333

53 3-(1,3- benzodioxol-5- yl)-N-(2- pyridylmethyl) imidazo[1,2-b]pyridazin-6- amine 0.79705 2.50 229_4007_0068

54 N-(cyclopropyl- methyl)-3-(3- methoxyphenyl) imidazo[1,2-b]pyridazin-6- amine 3.29534 2.91 229_4051_4140

55 3-[5-[(6- methoxy-3- pyridyl)amino] pyrazolo[1,5- a]pyrimidin-3-yl]phenol 3.39371 3.25 294_0042_0284

56 3-(3- methoxyphenyl)- N-(6-methoxy-3- pyridyl)pyrazolo [1,5-a]pyrimidin- 5-amine 5.3146 3.40 294_0042_4140

57 1-[3-[5-[(6- methoxy-3- pyridyl)amino] pyrazolo[1,5- a]pyrimidin-3-yl]phenyl] ethanone 1.63557 3.11 294_0042_4145

58 N-[5-[[3-(3- hydroxyphenyl) pyrazolo[1,5- a]pyrimidin-5- yl]amino]-2-methyl- phenyl]methane- sulfonamide 3.17096 2.92 294_0123_0284

59 3-(3,4- dimethoxy- phenyl)-N-(3- pyridylmethyl) pyrazolo[1,5-a]pyrimidin-5- amine 1.63605 2.56 294_4003_0079

60 N-(3- pyridylmethyl)- 3-(3,4,5- trimethoxy- phenyl) pyrazolo[1,5-a]pyrimidin-5- amine 2.35332 2.40 294_4003_0087

61 N-(4- isopropylphenyl)- 3-(4- methoxyphenyl) pyrazolo[1,5-a]pyrimidin-5- amine 4.17999 5.42 294_6937_0280

62 N-(2- furylmethyl)-3- phenyl- imidazo[1,2- b]pyridazin-6- amine6.37501 3.07 229_0144_0061

63 N-(2- furylmethyl)-3- (3,4,5- trimethoxyphenyl) imidazo[1,2-b]pyridazin-6- amine 4.89592 2.60 229_0144_0086

64 3-(3- aminophenyl)- N-(2- thienyimethyl) imidazo[1,2- b]pyridazin-6-amine 1.79421 3.10 229_0146_0005

65 N-(2- thienylmethyl)- 3-(3,4,5- trimethoxyphenyl) imidazo[1,2-b]pyridazin-6- amine 3.10009 3.45 229_0146_0087

66 3-(4- methoxyphenyl)- N-(2- thienylmethyl) imidazo[1,2-b]pyridazin-6- amine 5.3884 3.77 229_0146_0280

67 3-[6-(2- thienylmethyl- amino) imidazo[1,2- b]pyridazin-3- yl]phenol1.70365 3.62 229_0146_0284

68 2-[[3-(2- thienyl)imidazo [1,2-b]pyridazin- 6-yl]amino] butan-1-ol3.96823 2.31 229_0153_4147

69 N-[(3- chlorophenyl) methyl]-3-(4- methoxyphenyl) imidazo[1,2-b]pyridazin-6- amine 10.74649 4.46 229_0223_0280

70 N-[(3- chlorophenyl) methyl]-3-(6- methoxy-3- pyridyl)imidazo[1,2-b]pyridazin- 6-amine 8.33916 3.84 229_0223_0311

71 4-[6-[(3- chlorophenyl) methylamino] imidazo[1,2- b]pyridazin-3-yl]-2-methoxy- phenol 3.51753 4.15 229_0223_0314

72 3-(3- aminophenyl)- N-propyl- imidazo[1,2- b]pyridazin-6- amine0.93247 2.34 229_0226_0005

73 3-(1,3- benzodioxol-5- yl)-N-propyl- imidazo[1,2- b]pyridazin-6-amine 2.05098 2.79 229_0226_0068

74 N-propyl-3-(3- thienyl)imidazo [1,2-b]pyridazin- 6-amine 4.03981 2.95229_0226_0074

75 3-(3,4- dimethoxy- phenyl)-N- propyl- imidazo[1,2- b]pyridazin-6-amine 0.51897 2.85 229_0226_0079

76 N-[3-[6- (propylamino) imidazo[1,2- b]pyridazin-3- yl]phenyl]acetamide 0.62919 2.40 229_0226_0081

77 4-[6- (propylamino) imidazo[1,2- b]pyridazin-3- yl]benzoic acid9.76838 2.82 229_0226_0140

78 3-(4- methoxyphenyl)- N-propyl- imidazo[1,2- b]pyridazin-6- amine5.42987 3.01 229_0226_0280

79 3-[6- (propylamino) imidazo[1,2- b]pyridazin-3- yl]phenol 0.930032.86 229_0226_0284

80 3-(3- methoxyphenyl)- N-propyl- imidazo[1,2- b]pyridazin-6- amine2.21992 3.01 229_0226_4140

81 1-[3-[6- (propylamino) imidazo[1,2- b]pyridazin-3- yl]phenyl]ethanone 0.36718 2.72 229_0226_4145

82 4-[6-[(3,4- dichlorophenyl) methylamino] imidazo[1,2- b]pyridazin-3-yl]benzoic acid 1.00617 4.88 229_0227_0140

83 3-phenyl-N-(4- pyridylmethyl) imidazo[1,2- b]pyridazin-6- amine4.05638 2.79 229_0237_0061

84 3-(4- aminophenyl)-N- tetrahydropyran- 4-yl-imidazo[1,2-b]pyridazin-6- amine 3.12587 1.42 229_0242_0333

85 4-[6-[(2,4- dimethylphenyl) methylamino] imidazo[1,2- b]pyridazin-3-yl]-2-methoxy- phenol 5.30595 4.58 229_4319_0314

86 3-(5-methoxy-3- pyridyl)-N-(4- morpholino- phenyl)pyrazolo[1,5-a]pyrimidin- 5-amine 2.24998 2.85 294_0088_0196

87 3-(3-amino- phenyl)-N-(3- pyridylmethyl) pyrazolo[1,5- a]pyrimidin-5-amine 2.5122 2.05 294_4003_0005

88 3-(2- methoxyphenyl)- N-(3- pyridylmethyl) pyrazolo[1,5-a]pyrimidin-5- amine 1.22114 2.72 294_4003_0083

89 N-[3- (dimethylamino) propyl]-3-[6-(4- methoxyphenyl) pyrazin-2-yl]benzamide 9.05883 2.60 035_0280_0302

90 2-methoxy-4- [6-(4- methoxyphenyl) pyrazin-2- yl]phenol 5.17907 2.99035_0280_0314

91 N-[3-[6-(4- methoxyphenyl) pyrazin-2- yl]phenyl] acetamide 3.501362.68 035_0081_0280

92 N-[3-[6-(3- hydroxyphenyl) pyrazin-2- yl]phenyl] acetamide 3.878442.54 035_0081_0284

93 N-[3- (dimethylamino) propyl]-4-[6-(2- fluoro-3- methoxy- phenyl)-1H-pyrazolo[3,4- b]pyridin-3- yl]benzamide 7.3354 3.65 267_0180_7936

94 3-[2-amino-5- (3,4-dimethoxy- phenyl)-3- pyridyl]phenol 2.00489 3.20382_0284_0079

95 3-[6-amino-5-[3- (dimethylamino) phenyl]-3- pyridyl]-N-(2-hydroxyethyl) benzamide 3.57159 2.31 382_0135_0192

96 5-(3- methoxyphenyl)- 3-(3,4,5- trimethoxyphenyl) pyridin-2-amine9.5028 3.18 382_0087_4140

97 4-[2-amino-5-(4- methylsulfonyl- phenyl)-3-pyridyl]- 2-methoxy-phenol 0.34919 2.19 382_0314_0174

98 4-[2-amino-5-(p- tolyl)-3-pyridyl]- 2-methoxy- phenol 4.3442 3.87382_0314_4139

99 4-[2-amino-5-(3- chlorophenyl)-3- pyridyl]-2- methoxy-phenol 3.51073.96 382_0314_0279

100 4-[2-amino-5-(3- fluorophenyl)-3- pyridyl]-2- methoxy-phenol 2.027393.50 382_0314_0313

101 4-(2-amino-5- phenyl-3- pyridyl)-2- methoxy-phenol 1.47705 3.35382_0314_0061

102 4-[6-amino-5-(4- hydroxy-3- methoxy- phenyl)-3- pyridyl]-2,6-dimethyl-phenol 0.52648 4.08 382_0314_0315

103 4-[2-amino-5-(4- fluorophenyl)-3- pyridyl]-2- methoxy-phenol 3.240263.50 382_0314_0339

104 4-[2-amino-5- (3,4,5-trimethoxy- phenyl)-3- pyridyl]-2-methoxy-phenol 0.08059 2.88 382_0314_0087

105 4-[6-amino-5-[4- (methoxy- methoxy)phenyl]- 3-pyridyl] benzamide3.42268 2.57 382_0341_0346

106 [3-[6-amino-5-[4- (methoxymethoxy) phenyl]-3- pyridyl]phenyl]methanol 4.62016 2.95 382_0341_0291

107 3-[6-amino-5-[4- (methoxymethoxy) phenyl]-3- pyridyl]benzamide3.02265 2.57 382_0341_0347

108 N-[3-[6-amino-5- 4-(methoxy- methoxy) phenyl]-3- pyridyl]phenyl]acetamide 1.5493 2.96 382_0341_0081

109 4-[6-amino-5-[4- (hydroxymethyl) phenyl]-3- pyridyl]- 2,6-dimethyl-phenol 4.64395 3.77 382_0285_0315

110 3-[4- (methoxymethoxy) phenyl]-5- (3,4,5- trimethoxy-phenyl)pyridin- 2-amine 1.90467 3.25 382_0341_0087

111 3-[2-amino-5-(4- morpholino- phenyl)-3- pyridyl]phenol 4.64154 3.40382_0284_0001

112 N-[3-[6-amino- 5-(4- hydroxyphenyl)- 3-pyridyl]phenyl] acetamide0.83784 2.75 382_7249_0081

113 4-[2-amino-5- (3,4,5- trimethoxy- phenyl)-3- pyridyl]phenol 0.208863.04 382_7249_0087

114 4-[2-amino-5-[3- (dimethylamino) phenyl]-3- pyridyl]phenol 2.190693.62 382_7249_0135

115 3-[2-amino-5- (3,4,5- trimethoxy- phenyl)-3- pyridyl]phenol 1.015193.04 382_0284_0087

116 4-[2-amino-5-(4- methylsulfonyl- phenyl)-3- pyridyl]phenol 1.253392.35 382_7249_0174

117 3-(3- aminophenyl)-5- (3,4,5- trimethoxy- phenyl)pyridin- 2-amine2.96823 2.51 382_0005_0087

118 4-[2-amino-5-(3- methoxyphenyl)- 3-pyridyl]phenol 3.49074 3.35382_7249_4140

119 4-[6-amino-5-(4- pyridyl)-3- pyridyl]-2,6- dimethyl-phenol 1.704573.32 382_0069_0315

120 5-[6-[3- (dimethylamino) propoxy]-3- pyridyl]-3-(3,4,5- trimethoxy-phenyl)pyridin- 2-amine 0.5304 2.64 382_0087_0002

121 5-(3- fluorophenyl)-3- (3,4,5- trimethoxy- phenyl)pyridin- 2-amine1.5198 3.49 382_0087_0313

122 4-[6-amino-5- (3,4,5- trimethoxyphenyl)- 3-pyridyl]-2,6-dimethyl-phenol 0.71164 4.07 382_0087_0315

123 N-[3-[6-amino-5- (3,4,5-trimethoxy- phenyl)-3- pyridyl]phenyl]methane- sulfonamide 0.5248 1.72 382_0087_6488

124 5-phenyl-3- (3,4,5-trimethoxy- phenyl)pyridin- 2-amine 0.8934 3.34382_0087_0061

125 3-[6-amino-5- (3,4,5-trimethoxy- phenyl)-3- pyridyl]-N-(2-hydroxyethyl) benzamide 0.48532 1.73 382_0087_0192

126 5-(4- aminophenyl)- 3-(3,4,5- trimethoxy- phenyl)pyridin- 2-amine0.97087 2.51 382_0087_0333

127 4-[6-amino-5- (3,4,5-trimethoxy- phenyl)-3- pyridyl]phenol 1.725843.04 382_0087_7249

128 5-(4-fluoro- phenyl)-3- (3,4,5-trimethoxy- phenyl)pyridin- 2-amine2.85921 3.49 382_0087_0339

129 4-[6-amino-5- (3,4,5-trimethoxy- phenyl)-3- pyridyl]-N- cyclopropyl-benzamide 0.5072 2.88 382_0087_7489

130 5- (benzothiophen- 2-yl)-3-(3,4,5- trimethoxyphenyl) pyridin-2-amine2.69043 4.22 382_0087_0076

131 3-[6-amino-5- (3,4,5-trimethoxy- phenyl)-3- pyridyl]phenol 0.723223.04 382_0087_0284

132 5-(6-methoxy-3- pyridyl)-3-(3,4,5- trimethoxyphenyl) pyridin-2-amine1.06095 2.56 382_0087_0311

133 5-[3-(dimethyl- amino)phenyl]- 3-(3,4,5- trimethoxyphenyl)pyridin-2-amine 0.59506 3.45 382_0087_0135

134 [3-[6-amino-5-[3- (dimethylamino) phenyl]-3- pyridyl]phenyl]-(4-methyl- piperazin-1- yl)methanone 4.43871 3.07 382_0135_0200

135 4-[6-amino-5-[3- (dimethylamino) phenyl]-3- pyridyl]-2-methoxy-phenol 2.10895 3.46 382_0135_0314

136 3-[3-(dimethyl- amino)phenyl]- 5-(3,4,5- trimethoxy- phenyl)pyridin-2-amine 3.13462 3.45 382_0135_0087

137 4-[6-amino-5-[3- (dimethylamino) phenyl]-3- pyridyl]-2,6-dimethyl-phenol 4.20127 4.65 382_0135_0315

138 3-[3-(dimethyl- amino)phenyl]- 5-(3- pyridyl)pyridin- 2-amine7.11159 2.71 382_0135_0071

139 [3-[6-amino-5-[3- (dimethylamino) phenyl]-3- pyridyl]phenyl]methanol 2.6979 3.16 382_0135_0291

140 3-[3- (dimethylamino) phenyl]-5-[6- [3-(dimethyl- amino) propoxy]-3-pyridyl]pyridin- 2-amine 4.66462 3.22 382_0135_0002

141 3-[6-amino-5-[3- (dimethylamino) phenyl]-3- pyridyl] benzamide3.52109 2.77 382_0135_0347

142 5-(3,4- dimethoxy- phenyl)-3-[3- (dimethylamino) phenyl]pyridin-2-amine 5.04712 3.61 382_0135_0079

143 4-[2-amino-5-(3- chloro-4-fluoro- phenyl)-3- pyridyl]-2-methoxy-phenol 11.34048 4.10 382_0314_0164

144 5-(4- methoxyphenyl)- 3-(3,4,5- trimethoxy- phenyl)pyridin- 2-amine2.97729 3.18 382_0087_0280

145 4-[2-amino-5-(4- methoxyphenyl)- 3-pyridyl]-2- methoxy-phenol4.15847 3.20 382_0314_0280

146 5-(3-furyl)-3- (3,4,5-trimethoxy- phenyl)pyridin- 2-amine 12.09652.48 382_0087_0343

147 5-(2- phenoxyphenyl)- 3-(3,4,5- trimethoxy- phenyl)pyridin- 2-amine9.00592 4.84 382_0087_0063

148 4-[6-amino-5- (3,4,5-trimethoxy- phenyl)-3- pyridyl]benzamide0.40043 2.19 382_0087_0346

149 4-[2-amino-5-(3- methoxyphenyl)- 3-pyridyl]-2- methoxy-phenol1.19944 3.20 382_0314_4140

150 [4-[2-amino-5- (3,4-dimethoxy- phenyl)-3- pyridyl]phenyl] methanol5.13242 2.73 382_0285_0079

151 5-[4-(4- methylpiperazin- 1-yl)phenyl]-3- (3,4,5-trimethoxyphenyl)pyridin- 2-amine 0.32234 3.30 382_0087_0218

152 3-(4-fluoro- phenyl)-N-methyl- imidazo[1,2- b]pyridazin-6- amine3.25909 2.43 437_0339

153 3-(4- methoxyphenyl)- N-methyl- imidazo[1,2- b]pyridazin-6- amine4.15763 2.13 437_0280

154 2-[6- (methylamino) imidazo[1,2- b]pyridazin-3- yl]phenol 1.133951.98 437_0340

155 N-methyl-3-(3- thienyl)imidazo [1,2-b]pyridazin- 6-amine 4.231692.07 437_0074

156 3-[6-(methyl- amino) imidazo[1,2- b]pyridazin-3- yl]phenol 2.175881.98 437_0284

157 3-(3,4-dimethoxy phenyl)-N- methyl- imidazo[1,2- b]pyridazin-6-amine 1.24313 1.97 437_0079

158 N,N-dimethyl- 3-[6- (methylamino) imidazo[1,2- b]pyridazin-3-yl]benzamide 2.94156 1.59 437_0349

159 N-methyl-3-(1- methylpyrazol-4- yl)imidazo[1,2- b]pyridazin-6- amine5.63446 0.72 437_7468

160 N-[3-[6- (methylamino) imidazo[1,2- b]pyridazin-3- yl]phenyl]acetamide 1.75426 1.53 437_0081

161 3-(6-methoxy-3- pyridyl)-N- methyl- imidazo[1,2- b]pyridazin-6-amine 4.46164 1.51 437_0311

162 6-(1H-indol-5-yl)- N-methyl- pyrazin-2-amine 14.94246 1.74 445_0204

163 N-ethyl-2-(3,4,5- trimethoxy- anilino)-7,8- dihydro-5H- pyrido[4,3-d]pyrimidine-6- carboxamide 4.24682 1.18 582_9377_5725

164 6-propyl-N- (3,4,5-trimethoxy- phenyl)-7,8- dihydro-5H- pyrido[4,3-d]pyrimidin-2- amine 14.67829 2.59 582_9377_5632

165 [2-[3- (dimethylamino) anilino]-5,7- dihydropyrrolo[3,4-d]pyrimidin- 6-yl]-(2- methoxyphenyl) methanone 10.08397 2.97585_9372_5053

166 N-(2- hydroxyethyl)-4- [3-(4- hydroxyphenyl) imidazo[1,2-a]pyrazin-6- yl]benzamide 0.64093 1.22 388_0080_0328

167 3-[3-(4- hydroxyphenyl) imidazo[1,2- a]pyrazin-6-yl]- N,N-dimethyl-benzamide 0.97398 2.14 388_0080_0349

168 4-[6-[4-(4- isopropyl- piperazin-1- yl)phenyl]imidazo[1,2-a]pyrazin- 3-yl]phenol 0.63733 3.57 388_0080_0182

169 4-[6-(1- benzylpyrazol-4- yl)imidazo[1,2- a]pyrazin-3- yl]phenol6.6194 2.99 388_0080_7469

170 4-[3-(2- thienyl)imidazo [1,2-a]pyrazin-6- yl]phenol 6.25235 2.62388_4147_0080

171 3,6-bis(2- thienyl)imidazo [1,2-a]pyrazine 5.02752 2.70388_4147_4147

172 N-(2-hydroxy- ethyl)-3-[3-(4- hydroxyphenyl) imidazo[1,2-a]pyrazin-6- yl]benzamide 1.03081 1.22 388_0080_0192

173 N-cyclopropyl-4- [3-(4- hydroxyphenyl) imidazo[1,2- a]pyrazin-6-yl]benzamide 1.95812 2.38 388_0080_7489

174 4-[6-[4-(4- methyl- piperazin-1- yl)phenyl]imidazo [1,2-a]pyrazin-3-yl]phenol 0.67809 2.79 388_0080_0218

175 4-[6-(6-amino-3- pyridyl)imidazo [1,2-a]pyrazin- 3-yl]phenol 1.93271.39 388_0080_7905

176 5-[3-(2- thienyl)imidazo [1,2-a]pyrazin-6- yl]pyridin-2- amine8.16191 1.47 388_4147_7905

177 4-[3-(3- acetylphenyl) imidazo[1,2- a]pyrazin-6-yl]- N-(2-dimethyl-aminoethyl) benzamide 4.07021 1.79 388_4145_0327

178 N-(2- dimethylamino- ethyl)-4-[3-(2- thienyl)imidazo [1,2-a]pyrazin-6-yl]benzamide 8.52139 2.01 388_4147_0327

179 4-[3-(3,5- dimethoxyphenyl) imidazo[1,2- a]pyrazin-6-yl]-N-[3-(dimethyl- amino)propyl] benzamide 6.69112 1.98 388_7492_0180

180 N-(2- dimethylamino- ethyl)-4-[3-(4- pyridyl)imidazo[1,2-a]pyrazin-6- yl]benzamide 6.90909 1.02 388_0069_0327

181 4-[6-[2- (dimethylamino) phenyl]imidazo [1,2-a]pyrazin-3-yl]-2-methoxy- phenol 1.75434 2.79 388_0314_0006

182 N-(2- hydroxyethyl)-3- [3-(4-hydroxy-3- methoxy- phenyl)imidazo[1,2-a]pyrazin-6- yl]benzamide 0.8957 1.07 388_0314_0192

183 2-methoxy-4-[6- (3-pyridyl) imidazo[1,2- a]pyrazin-3- yl]phenol3.06577 1.46 388_0314_0071

184 4-[6-(2- chlorophenyl) imidazo[1,2- a]pyrazin-3-yl]-2-methoxy-phenol 2.53905 3.28 388_0314_4027

185 4-[6-(3- ethoxyphenyl) imidazo[1,2- a]pyrazin-3-yl]- 2-methoxy-phenol 1.36347 2.88 388_0314_0205

186 N-(2- dimethylamino- ethyl)-4-[3-(4- hydroxy-3- methoxy-phenyl)imidazo [1,2-a]pyrazin-6- yl]benzamide 0.44033 1.77 388_0314_0327

187 4-[6-(6-amino-3- pyridyl)imidazo [1,2-a]pyrazin-3- yl]-2-methoxy-phenol 1.41172 1.23 388_0314_7905

188 2-methoxy-4-[6- [6-(4- methylpiperazin- 1-yl)-3- pyridyl]imidazo[1,2-a]pyrazin- 3-yl]phenol 1.13372 2.01 388_0314_0016

189 2-methoxy-4-[6- (1-methylpyrazol- 4-yl)imidazo[1,2- a]pyrazin-3-yl]phenol 0.74595 1.11 388_0314_8400

190 N-[3-[3-(3,4,5- trimethoxyphenyl) imidazo[1,2- a]pyrazin-6-yl]phenyl] methane- sulfonamide 2.79564 1.04 388_0087_6488

191 N-[3- (dimethylamino) propyl]-4-[3-(4- hydroxy-3- methoxy-phenyl)imidazo [1,2-a]pyrazin-6- yl]benzamide 0.60574 1.83 388_0314_0180

192 2-methoxy-4-[6- [6-(2- morpholinoethyl- amino)-3- pyridyl]imidazo[1,2-a]pyrazin- 3-yl]phenol 1.35363 1.33 388_0314_0003

193 6-(1- methylpyrazol-4- yl)-3-(3- thienyl)imidazo [1,2-a]pyrazine6.37648 1.35 388_0074_8400

194 6-phenyl-3-(3- thienyl)imidazo [1,2-a]pyrazine 3.94995 2.92388_0074_0061

195 [4-[3-(3- thienyl)imidazo [1,2-a]pyrazin- 6-yl]phenyl] methanol2.3518 2.16 388_0074_0285

196 4-[3-(4- methoxyphenyl) imidazo[1,2- a]pyrazin-6- yl]phenol 10.458262.68 388_0280_0080

197 6-(3-pyridyl)-3- (3- thienyl)imidazo [1,2-a]pyrazine 4.33598 1.70388_0074_0071

198 3-(4-pyridyl)-6- (2- thienyl)imidazo [1,2-a]pyrazine 5.68757 1.70388_0069_4147

199 4-[3-(3- thienyl)imidazo [1,2-a]pyrazin-6- yl]phenol 2.70168 2.62388_0074_0080

200 6-(2-thienyl)-3- (3- thienyl)imidazo [1,2-a]pyrazine 2.24904 2.70388_0074_4147

201 N-[3-[3-(3- thienyl)imidazo [1,2-a]pyrazin-6- yl]phenyl] acetamide2.32941 2.16 388_0074_0081

202 N-[3-[3-(3- thienyl)imidazo [1,2-a]pyrazin-6- yl]phenyl] methane-sulfonamide 3.32047 1.30 388_0074_6488

203 6-(2-furyl)-3-(3- thienyl)imidazo [1,2-a]pyrazine 6.25008 1.98388_0074_0142

204 3-(6- phenylimidazo [1,2-a]pyrazin- 3-yl)phenol 6.54588 2.84388_0284_0061

205 3-[3-(3- hydroxyphenyl) imidazo[1,2- a]pyrazin-6- yl]benzamide1.58014 1.69 388_0284_0347

206 4-[6-(3- pyridyl)imidazo [1,2-a]pyrazin- 3-yl]phenol 2.72591 1.62388_0080_0071

207 4-[3-(4- phenoxyphenyl) imidazo[1,2- a]pyrazin-6- yl]phenyl]methanol 4.72246 3.88 388_1029_0285

208 4-[6-(4- chlorophenyl) imidazo[1,2- a]pyrazin-3- yl]phenol 6.378383.44 388_0080_0160

209 3-[6-(2- thienyl)imidazo [1,2-a]pyrazin- 3-yl]phenol 2.78435 2.62388_0284_4147

210 6-(1- methylpyrazol- 4-yl)-3-(4- phenoxyphenyl) imidazo[1,2-a]pyrazine 1.92958 3.07 388_1029_8400

211 3-[6-(2- furyl)imidazo [1,2-a]pyrazin- 3-yl]phenol 6.11196 1.90388_0284_0142

212 4-[6-(6-methoxy- 3- pyridyl)imidazo [1,2-a]pyrazin- 3-yl]phenol1.97871 2.06 388_0080_0311

213 3-[6-[4- (hydroxymethyl) phenyl]imidazo [1,2-a]pyrazin- 3-yl]phenol3.35687 2.07 388_0284_0285

214 3-[6-(1- methylpyrazol-4- yl)imidazo[1,2- a]pyrazin-3- yl]phenol2.78229 1.27 388_0284_8400

215 4-[6-(1- methylpyrazol-4- yl)imidazo[1,2- a]pyrazin-3- yl]phenol1.58926 1.27 388_0080_8400

216 6-[6-(4- methylpiperazin- 1-yl)-3-pyridyl]- 3-(4- phenoxyphenyl)imidazo[1,2- a]pyrazine 2.13162 3.97 388_1029_0016

217 N-(2- hydroxyethyl)- 3-[3-(4- phenoxyphenyl) imidazo[1,2-a]pyrazin-6- yl]benzamide 1.48118 3.03 388_1029_0192

218 N-(2- dimethylamino- ethyl)-4-[3-(4- phenoxyphenyl) imidazo[1,2-a]pyrazin-6- yl]benzamide 0.1649 3.74 388_1029_0327

219 N-(2- hydroxyethyl)-4- [3-(4- phenoxyphenyl) imidazo[1,2-a]pyrazin-6- yl]benzamide 0.62307 3.03 388_1029_0328

220 4-[3-(3- chlorophenyl) imidazo[1,2- a]pyrazin-6-yl]- N-[3-(dimethylamino) propyl]benzamide 8.43215 2.90 388_0279_0180

221 5-[3-(4- phenoxyphenyl) imidazo[1,2- a]pyrazin-6- yl]pyridin-2-amine 1.71808 3.19 388_1029_7905

222 N-[3- (dimethylamino) propyl]-4-[3-(3- thienyl)imidazo[1,2-a]pyrazin-6- yl]benzamide 3.87213 2.08 388_0074_0180

223 3-(4- methoxyphenyl)- 6-[4-(4-methyl- piperazin-1- yl)phenyl]imidazo[1,2- a]pyrazine 5.25112 2.94 388_0280_0218

224 N-(2- hydroxyethyl)-3- [3-(3- thienyl)imidazo [1,2-a]pyrazin-6-yl]benzamide 3.67126 1.31 388_0074_0192

225 6-[6-(4- methylpiperazin- 1-yl)-3-pyridyl]-3- (3- thienyl)imidazo[1,2-a]pyrazine 7.04574 2.25 388_0074_0016

226 5-[3-(3- thienyl)imidazo [1,2-a]pyrazin- 6-yl]pyridin-2- amine2.45583 1.47 388_0074_7905

227 3,6-bis(3- thienyl)imidazo [1,2-a]pyrazine 8.47406 2.70388_0074_0074

228 N-(2- dimethylamino- ethyl)-4-[3-(3- thienyl)imidazo [1,2-a]pyrazin-6-yl]benzamide 1.89752 2.02 388_0074_0327

229 3-(1- methylpyrazol-4- yl)-6-(2- phenoxyphenyl) imidazo[1,2-a]pyrazine 1.81873 3.07 388_8400_0063

230 3-[6-[6-(4- methylpiperazin- 1-yl)-3- pyridyl]imidazo[1,2-a]pyrazin- 3-yl]phenol 3.14141 2.17 388_0284_0016

231 3-[[5-[3-(1,3- benzodioxol-5- yl)imidazo[1,2- a]pyrazin-6-yl]-2-pyridyl]oxy]- N,N-dimethyl- propan-1-amine 9.85132 2.06 388_0068_0002

232 3-[6-(3- ethoxyphenyl) imidazo[1,2- a]pyrazin-3- yl]phenol 6.68593.04 388_0284_0205

233 3-(1,3- benzodioxol-5- yl)-6-[4-(4- methylpiperazin- 1-yl)phenyl]imidazo[1,2- a]pyrazine 7.93105 2.72 388_0068_0218

234 3-[6-(3- thienyl)imidazo [1,2-a]pyrazin- 3-yl]phenol 2.51787 2.62388_0284_0074

235 3-[6-[4-(4- methyl- piperazin-1- yl)phenyl]imidazo [1,2-a]pyrazin-3-yl]phenol 1.58793 2.79 388_0284_0218

236 4-[3-(4- chlorophenyl) imidazo[1,2- a]pyrazin-6-yl]- N-[3-(dimethylamino) propyl]benzamide 4.90272 2.90 388_0160_0180

237 4-[3-(1,3- benzodioxol-5- yl)imidazo[1,2- a]pyrazin-6-yl]-N-(2-dimethyl- aminoethyl) benzamide 3.79881 1.86 388_0068_0327

238 3-[6-(6-amino-3- pyridyl)imidazo [1,2-a]pyrazin-3- yl]phenol 2.888771.39 388_0284_7905

239 N-(2- dimethylamino- ethyl)-4-[3-(3- hydroxyphenyl) imidazo[1,2-a]pyrazin-6- yl]benzamide 0.81226 1.93 388_0284_0327

240 4-[3-(4- chlorophenyl) imidazo[1,2- a]pyrazin-6-yl]- N-(2-dimethylamino- ethyl)benzamide 4.15862 2.84 388_0160_0327

241 3-[6-[6-(2- morpholino- ethylamino)-3- pyridyl]imidazo[1,2-a]pyrazin-3- yl]phenol 2.93938 1.49 388_0284_0003

242 N-[3- (dimethylamino) propyl]-4-[3-(3- hydroxyphenyl) imidazo[1,2-a]pyrazin-6- yl]benzamide 1.61113 1.99 388_0284_0180

243 N-(2- hydroxyethyl)-4- [3-(3- hydroxyphenyl) imidazo[1,2-a]pyrazin-6- yl]benzamide 1.72336 1.22 388_0284_0328

244 4-[3-(1,3- benzodioxol-5- yl)imidazo[1,2- a]pyrazin-6-yl]- N-[3-(dimethylamino) propyl]benzamide 6.03233 1.92 388_0068_0180

245 6-[6-(4- methylpiperazin- 1-yl)-3-pyridyl]- 3-phenyl- imidazo[1,2-a]pyrazine 10.85328 2.47 388_0061_0016

246 3-[6-[4-(4- isopropyl- piperazin-1- yl)phenyl]imidazo[1,2-a]pyrazin- 3-yl]phenol 2.61352 3.57 388_0284_0182

247 5-[3-(1,3- benzodioxol-5- yl)imidazo[1,2- a]pyrazin-6- yl]pyridin-2-amine 10.23913 1.31 388_0068_7905

248 4-[6-[6-[3- (dimethylamino) propoxy]-3- pyridyl]imidazo[1,2-a]pyrazin- 3-yl]phenol 1.32178 2.14 388_0080_0002

249 4-[6-[6-(2- morpholino- ethylamino)-3- pyridyl]imidazo[1,2-a]pyrazin- 3-yl]phenol 1.31444 1.49 388_0080_0003

250 4-[6-[6-(4- methylpiperazin- 1-yl)-3- pyridyl]imidazo[1,2-a]pyrazin- 3-yl]phenol 2.21078 2.17 388_0080_0016

251 3-[2-(cyclo- hexylamino) imidazo[2,1-a] [1,3,4]thiadiazol-5-yl]-N,N- dimethyl- benzamide 0.71795 3.60 699_0052_0349

252 N,N-dimethyl-3- [2-[2-(4- sulfamoylphenyl) ethylamino]imidazo[2,1-a] [1,3,4]thiadiazol- 5-yl]benzamide 0.9091 2.42699_6182_0349

253 3-[2-[(4- hydroxycyclo- hexyl)amino] imidazo[2,1-b][1,3,4]thiadiazol- 5-yl]-N,N- dimethyl- benzamide 0.53282 2.22699_0240_0349

254 1-[3-[2-[(4- hydroxycyclo- hexyl)amino] imidazo[2,1-a][1,3,4]thiadiazol- 5-yl]phenyl] ethanone 0.48712 2.48 699_0240_4145

255 6-(3- chlorophenyl)- 3-(3,4- dimethoxyphenyl) pyrazolo[1,5-a]pyrimidin-7- amine 0.80424 3.50 DT2008- 0028664

256 N-[3-[2-(2- furylmethylamino) imidazo[2,1-a] [1,3,4]thiadiazol-5-yl]phenyl] acetamide 4.56802 2.53 699_0144_0081

257 3-[2- (cyclopropyl- methylamino) imidazo[2,1-d] [1,3,4]thiadiazol-5-yl]-N,N- dimethyl- benzamide 0.97667 2.59 699_4051_0349

258 3-[2- (isobutylamino) imidazo[2,1-d] [1,3,4]thiadiazol- 5-yl]-N,N-dimethyl- benzamide 0.28265 3.05 699_0149_0349

259 3-[2-[(4- fluorophenyl) methylamino] imidazo[2,1-b][1,3,4]thiadiazol- 5-yl]-N,N- dimethyl- benzamide 2.76099 3.67699_0224_0349

260 N-[3-[2-(2- thienylmethyl- amino)imidazo [2,1-b] [1,3,4]thiadiazol-5-yl]phenyl] acetamide 3.92554 3.38 699_0146_0081

261 4-[2-[[5-(1- methylpyrazol- 4-yl)imidazo[2,1- d][1,3,4]thiadiazol-2- yl]amino]ethyl] benzene- sulfonamide 2.26191 1.55699_6182_7468

262 4-[[5-[3- (dimethylamino) phenyl]imidazo [2,1-a] [1,3,4]thiadiazol-2-yl]amino] cyclohexanol 5.79421 3.03 699_0240_0135

263 N-[3-[2- (isobutylamino) imidazo[2,1-b] [1,3,4]thiadiazol-5-yl]phenyl] methane- sulfonamide 7.06833 2.12 699_0149_6488

264 3-[2-(3- hydroxypropyl- amino)imidazo [2,1-b][1,3,4] thiadiazol-5-yl]benzamide 2.87875 0.73 699_0248_0347

265 4-[2-[(4- hydroxycyclo- hexyl)amino] imidazo[2,1-b][1,3,4]thiadiazol- 5-yl]phenol 3.804 2.62 699_0240_0080

266 3-[2-(2- furylmethyl- amino) imidazo[2,1-b] [1,3,4]thiadiazol-5-yl]benzamide 1.22619 2.14 699_0144_0347

267 4-[2-[[5-(6- methoxy-3- pyridyl)imidazo [2,1-b] [1,3,4]thiadiazol-2-yl]amino] ethyl]benzene- sulfonamide 2.61127 2.35 699_6182_0311

268 N,N-dimethyl-3- [2-(tetrahydro- pyran-4- ylmethylamino)imidazo[2,1-b] [1,3,4]thiadiazol- 5-yl]benzamide 2.72692 2.23699_0243_0349

269 N,N-dimethyl-3- [2-(o-tolyl- methylamino) imidazo[2,1-b][1,3,4]thiadiazol- 5-yl]benzamide 3.73043 4.04 699_8074_0349

270 N-isobutyl-5-(5- methoxy-3- pyridyl)imidazo [2,1-b][1,3,4]thiadiazol- 2-amine 5.16693 2.38 699_0149_0196

271 N-(1,3- benzodioxol-5- ylmethyl)-5-(5- methoxy-3- pyridyl)imidazo[2,1-b] [1,3,4]thiadiazol- 2-amine 0.44781 2.48 699_0236_0196

272 N-[4-[3-(4- hydroxy-3- methoxy- phenyl)imidazo [1,2-b]pyridazin-6-yl]phenyl] acetamide 0.16907 3.03 828_0314_0722

273 N-[3-[6-(1,3- benzodioxol-5- yl)imidazo[1,2- b]pyridazin-3-yl]phenyl] acetamide 1.16817 3.11 828_0081_0068

274 N-[3-[3-(1,3- benzodioxol-5- yl)imidazo[1,2- b]pyridazin-6-yl]phenyl] acetamide 1.10979 3.11 828_0068_0081

275 N-[3-(3- acetylphenyl)-6- 4-(morpholine-4- carbonyl)phenyl]imidazo[1,2- a]pyridin-8- yl]acetamide 2.02757 1.85 802_4145_0337

276 N-[3-[6-[3- (trifluoromethoxy) phenyl]imidazo [1,2-b]pyridazin-3-yl]phenyl] acetamide 1.5009 4.92 828_0081_0168

277 1-[3-[6-(3,4- dimethoxyphenyl) imidazo[1,2- b]pyridazin-3-yl]phenyl] ethanone 0.65302 3.50 828_4145_0079

278 N-[3-[6-(4- methylsulfonyl- phenyl)imidazo [1,2-b]pyridazin-3-yl]phenyl] acetamide 1.08226 2.33 828_0081_0174

279 N-[3-[3-(3- acetamidophenyl) imidazo[1,2-b] pyridazin-6- yl]phenyl]acetamide 0.55312 2.73 828_0081_0081

280 3-[2-[(4- methoxyphenyl) methylamino] imidazo[2,1-b][1,3,4]thiadiazol- 5-yl]-N,N- dimethyl- benzamide 2.33054 3.37699_0244_0349

281 N-[3-[3-(3- acetylphenyl) imidazo[1,2- b]pyridazin-6- yl]phenyl]acetamide 0.6205 3.05 828_4145_0081

282 4-[3-(3- acetamidophenyl) imidazo[1,2- b]pyridazin-6- yl]benzamide0.22155 2.34 828_0081_0346

283 N-[4-[3-(3- hydroxyphenyl) imidazo[1,2- b]pyridazin-6- yl]phenyl]acetamide 0.51873 3.19 828_0284_0722

284 N-[2-(4- pyridyl)ethyl]-5- (3,4,5- trimethoxy- phenyl)imidazo[2,1-b][1,3,4] thiadiazol-2- amine 1.77014 2.83 699_0039_0087

285 N-[3-(4- fluorophenyl)-6- [4-(morpholine-4- carbonyl)phenyl]imidazo[1,2- a]pyridin-8- yl]formamide 3.59432 2.39 788_0339_0337

286 3-[2- (benzylamino) imidazo[2,1-d] [1,3,4]thiadiazol- 5-yl]-N,N-dimethyl- benzamide 1.50507 3.53 699_0232_0349

287 5-(6-methoxy-3- pyridyl)-N-(4- pyridylmethyl) imidazo[2,1-b][1,3,4]thiadiazol- 2-amine 2.58601 2.23 699_0237_0311

288 N-[3-[3-[3- (hydroxymethyl) phenyl]imidazo [1,2-b]pyridazin-6-yl]phenyl] acetamide 1.63929 2.72 828_0291_0081

289 3-[2-(2- furylmethylamino) imidazo[2,1-p] [1,3,4]thiadiazol-5-yl]-N,N- dimethyl- benzamide 2.46273 2.59 699_0144_0349

290 N-[3-[6-(4- dimethylamino- phenyl)imidazo [1,2-a]pyridazin-3-yl]phenyl] acetamide 1.09863 3.60 828_0081_0004

291 N-[3-(3- acetylphenyl)-6- [4-(morpholine-4- carbonyl)phenyl]imidazo[1,2- a]pyridin-8- yl]formamide 2.99487 1.80 788_4145_0337

292 N-[3-[3-(4- hydroxy-3- methoxy- phenyl)imidazo [1,2-b]pyridazin-6-yl]phenyl] acetamide 0.10208 3.03 828_0314_0081

293 N-[3-[3-[4- (hydroxymethyl) phenyl]imidazo [1,2-b]pyridazin-6-yl]phenyl] methane- sulfonamide 0.83024 1.86 828_0285_6488

294 1-[3-[6-(3- hydroxyphenyl) imidazo[1,2- a]pyridazin-3- yl]phenyl]ethanone 0.99396 3.51 828_4145_0284

295 [4-[3-[3- (hydroxymethyl) phenyl]imidazo [1,2-b]pyridazin-6-yl]phenyl] methanol 2.22994 2.72 828_0291_0285

296 4-[3-[3- (hydroxymethyl) phenyl]imidazo [1,2-b]pyridazin-6-yl]benzamide 1.89185 2.34 828_0291_0346

297 N-(2- dimethylamino- ethyl)-3-[6-[4- (hydroxymethyl) phenyl]imidazo[1,2-b]pyridazin- 3-yl]benzamide 1.47637 2.58 828_0176_0285

298 3-[3-(3- hydroxyphenyl) imidazo[1,2- b]pyridazin-6- yl]benzamide0.31104 2.80 828_0284_0347

299 4-[3-[4- (hydroxymethyl) phenyl]imidazo [1,2-b]pyridazin-6-yl]-2-methoxy- phenol 0.22297 3.02 828_0285_0314

300 2-(3,4- dimethoxy- phenyl)-6- hydroxy- chromen-4-one 8.95228 2.35DT2012- 0347380

301 [3-[6-(3- pyridyl)imidazo [1,2-b]pyridazin- 3-yl]phenyl] methanol2.03689 2.27 828_0291_0071

302 [3-[6-[(4- fluorophenyl) methyl]imidazo [1,2-b]pyridazin-3-yl]phenyl] methanol 3.9747 3.56 828_0291_6370

303 [3-[6-(3- methoxyphenyl) imidazo[1,2- b]pyridazin-3- yl]phenyl]methanol 2.74495 3.33 828_0291_4140

304 N-[3-[3-(4- pyridyl)imidazo [1,2-b]pyridazin- 6-yl]phenyl] methane-sulfonamide 0.29796 1.41 828_0069_6488

305 1-benzyl-N-[4- (4-methyl- piperazin-1-yl) phenyl]-2-(3-pyridyl)pyrrolo [3,2-c]pyridin-6- amine 13.73604 5.14 809_2675_6001_0091

306 2-(1H-pyrazol-4- yl)-N-(2-pyridyl)- 1H-pyrrolo[3,2-c]pyridin-6-amine 7.566 2.14 809_2678_0263_0259

307 N-(4-methyl- sulfonylphenyl)- 2-(1H-pyrazol- 4-yl)-1H- pyrrolo[3,2-c]pyridin-6-amine 4.77594 1.60 809_2678_0263_9248

308 1-benzyl-2-(3- pyridyl)-N- pyrimidin-4-yl- pyrrolo[3,2-c]pyridin-6-amine 6.84653 3.86 809_2675_6001_6410

309 N-(3- methoxyphenyl)- 2-(1H-pyrazol-4- yl)-1H- pyrrolo[3,2-c]pyridin-6-amine 16.58236 2.60 809_2678_0263_0026

310 N-(3,4- dimethoxy- phenyl)-2-(1H- pyrazol-4-yl)- 1H-pyrrolo[3,2-2]pyridin-6- amine 12.71137 2.44 809_2678_0263_0036

311 1-benzyl-N-[4-(4- methylpiperazin- 1-yl)phenyl]-2- phenyl-pyrrolo[3,2- c]pyridin-6-amine 15.018 6.36 809_9960_6001_0091

312 6-(2- methoxyphenyl)- 3-(4- pyridyl)imidazo [1,2-b]pyridazine0.58491 2.88 828_0069_0083

313 3-[3-(4- pyridyl)imidazo [1,2-b]pyridazin- 6-yl]benzamide 1.20241.89 828_0069_0347

314 N-[3-(6- phenylimidazo [1,2-b]pyridazin- 3-yl)phenyl] acetamide0.77278 3.49 828_0081_0061

315 N-[3-[6-(3- hydroxyphenyl) imidazo[1,2- b]pyridazin-3- yl]phenyl]acetamide 1.0711 3.19 828_0081_0284

316 3-(3,4- dimethoxy- phenyl)-6-(3- fluorophenyl) imidazo[1,2-b]pyridazine 1.0392 4.08 828_0079_0313

317 N-[3-[6-[4- (hydroxymethyl) phenyl]imidazo [1,2-b]pyridazin-3-yl]phenyl] acetamide 0.49363 2.72 828_0081_0285

318 [3-(6- phenylimidazo [1,2-b]pyridazin- 3-yl)phenyl] methanol 1.745263.49 828_0291_0061

319 6-(3- chlorophenyl)-3- (4-pyridyl)imidazo [1,2-b]pyridazine 0.258193.64 828_0069_0279

320 4-[3-(3,4- dimethoxy- phenyl)imidazo [1,2-b]pyridazin-6-yl]-2-methoxy- phenol 0.22231 3.48 828_0079_0314

321 N-[3-[6-(2- methoxyphenyl) imidazo[1,2- b]pyridazin-3- yl]phenyl]acetamide 2.85447 3.33 828_0081_0083

322 N-[3-[6-[3- (trifluoromethyl) phenyl]imidazo [1,2-b]pyridazin-3-yl]phenyl] acetamide 1.6027 4.37 828_0081_0312

323 [3-[6-(2- methoxyphenyl) imidazo[1,2- b]pyridazin-3- yl]phenyl]methanol 1.06972 3.33 828_0291_0083

324 4-[3-[3- (hydroxymethyl) phenyl]imidazo [1,2-b]pyridazin-6-yl]-2-methoxy- phenol 0.15309 3.02 828_0291_0314

325 3-phenyl-6-(4- pyridyl)imidazo [1,2-b]pyridazine 6.92543 3.04828_0061_0069

326 3-[3-(4- pyridyl)imidazo [1,2-b]pyridazin- 6-yl]phenol 0.22268 2.73828_0069_0284

327 3-(3,4- dimethoxy- phenyl)-6- phenyl- imidazo[1,2- b]pyridazine0.42017 3.94 828_0079_0061

328 3-(3,4- dimethoxy- phenyl)-6-(4- fluorophenyl) imidazo[1,2-b]pyridazine 1.33171 4.08 828_0079_0339

329 N-[3-[6-(3,4,5- trimethoxyphenyl) imidazo[1,2- b]pyridazin-3-yl]phenyl] acetamide 3.13438 3.02 828_0081_0087

330 N-[3-[6-(4- hydroxy-3- methoxy- phenyl)imidazo [1,2-b]pyridazin-3-yl]phenyl] acetamide 0.09296 3.03 828_0081_0314

331 3-phenyl-6-(3- pyridyl)imidazo [1,2-b]pyridazine 3.84274 3.04828_0061_0071

332 4-[3-(4- pyridyl)imidazo [1,2-b]pyridazin- 6-yl]phenyl] methanol0.2553 2.27 828_0069_0285

333 3-(3,4- dimethoxy- phenyl)-6-(2- methoxyphenyl) imidazo[1,2-b]pyridazine 3.12222 3.78 828_0079_0083

334 3-(3,4- dimethoxy- phenyl)-6-(3- furyl)imidazo [1,2- b]pyridazine0.98263 3.08 828_0079_0343

335 N-[3-[6-(3- furyl)imidazo [1,2-b]pyridazin- 3-yl]phenyl] acetamide1.2569 2.63 828_0081_0343

336 [3-[6-(3- furyl)imidazo [1,2-b]pyridazin- 3-yl]phenyl] methanol3.99398 2.63 828_0291_0343

337 N,N-dimethyl-4- [3-(4-pyridyl) imidazo[1,2-b] pyridazin-6-yl]aniline 0.39834 3.14 828_0069_0004

338 [3-[6-(4- methylsulfonyl- phenyl)imidazo [1,2-b]pyridazin-3-yl]phenyl] methanol 3.03776 2.33 828_0291_0174

339 N-[3-(3- phenylimidazo [1,2-b]pyridazin- 6-yl)phenyl] acetamide3.66176 3.49 828_0061_0081

340 6-phenyl-3-(4- pyridyl)imidazo [1,2-b]pyridazine 0.22894 3.04828_0069_0061

341 6-(3- fluorophenyl)-3- (4-pyridyl) imidazo[1,2- b]pyridazine 0.356113.18 828_0069_0313

342 3-(3,4- dimethoxy- phenyl)-6-(3- methoxyphenyl) imidazo[1,2-b]pyridazine 0.95169 3.78 828_0079_4140

343 N-[3-[6-(5- methoxy-3- pyridyl)imidazo [1,2-b]pyridazin-3-yl]phenyl] acetamide 0.614 2.12 828_0081_0196

344 3-[6-(5-methoxy- 3-pyridyl) imidazo[1,2- b]pyridazin-3- yl]phenyl]methanol 2.14052 2.11 828_0291_0196

345 6-(1,3- benzodioxol-5- yl)-3-(4- pyridyl)imidazo [1,2-b]pyridazine0.21745 2.66 828_0069_0068

346 6-(3-furyl)-3-(4- pyridyl)imidazo [1,2-b]pyridazine 1.02049 2.18828_0069_0343

347 N-[3-[6-(3- chlorophenyl) imidazo[1,2- b]pyridazin-3- yl]phenyl]acetamide 0.3705 4.10 828_0081_0279

348 N-[3-[6-(3- methoxyphenyl) imidazo[1,2- b]pyridazin-3- yl]phenyl]acetamide 0.40863 3.33 828_0081_4140

349 3-[3-[3- (hydroxymethyl) phenyl]imidazo [1,2-b]pyridazin-6-yl]phenol 0.95381 3.18 828_0291_0284

350 4-(3- phenylimidazo [1,2-b]pyridazin- 6-yl)benzamide 2.14265 3.10828_0061_0346

351 3-[3-(1,3- benzodioxol-5- yl)imidazo[1,2- b]pyridazin-6- yl]phenol0.91497 3.57 828_0068_0284

352 6-phenyl-3-(3- pyridyl)imidazo [1,2-b]pyridazine 1.94131 3.04828_0071_0061

353 3-(3-pyridyl)-6- (2-thienyl) imidazo[1,2-b] pyridazine 0.34617 2.81828_0071_4147

354 N-[3-[6-(3- acetylphenyl) imidazo[1,2- b]pyridazin-3- yl]phenyl]acetamide 0.46574 3.05 828_0081_4145

355 3-[6-(3- methoxyphenyl) imidazo[1,2- b]pyridazin-3- yl]phenol 1.23573.79 828_0284_4140

356 4-[6-(3,4- dimethoxyphenyl) imidazo[1,2- b]pyridazin-3-yl]-2-methoxy- phenol 0.04451 3.48 828_0314_0079

357 1-[3-[6-(2- methoxyphenyl) imidazo[1,2- b]pyridazin-3- yl]phenyl]ethanone 2.3343 3.65 828_4145_0083

358 1-[3-[6-(1- methylpyrazol-4- yl)imidazo[1,2- 3]pyridazin-3-yl]phenyl] ethanone 0.37322 2.24 828_4145_7468

359 N-[3-[3-(2- thienyl)imidazo [1,2-b]pyridazin- 6-yl]phenyl] methane-sulfonamide 1.20815 2.40 828_4147_6488

360 3-(1,3- benzodioxol-5- yl)-6-(3- pyridyl)imidazo [1,2-b]pyridazine0.68757 2.66 828_0068_0071

361 [4-[3-(3- pyridyl)imidazo [1,2-b]pyridazin- 6-yl]phenyl] methanol2.9094 2.27 828_0071_0285

362 6-benzyl-3-(3,4- dimethoxyphenyl) imidazo[1,2- b]pyridazine 0.974483.87 828_0079_6001

363 3-[6-[4- (hydroxymethyl) phenyl]imidazo [1,2-b]pyridazin-3-yl]phenol 0.28545 3.18 828_0284_0285

364 4-[6-(2- methoxyphenyl) imidazo[1,2- 3]pyridazin-3- yl]phenyl]methanol 3.90029 3.33 828_0285_0083

365 [4-[6-(3- methoxyphenyl) imidazo[1,2- b]pyridazin-3- yl]phenyl]methanol 1.55838 3.33 828_0285_4140

366 2-methoxy-4-[6- (3-methoxyphenyl) imidazo[1,2- b]pyridazin-3-yl]phenol 0.22071 3.63 828_0314_4140

367 1-[3-[6- (3-furyl)imidazo [1,2-b]pyridazin- 3-yl]phenyl] ethanone3.4398 2.95 828_4145_0343

368 4-[3-(2- thienyl)imidazo [1,2-b]pyridazin- 6-yl]benzamide 0.951012.88 828_4147_0346

369 3-[3-(1,3- benzodioxol-5- yl)imidazo[1,2- b]pyridazin-6- yl]-N-(2-hydroxyethyl) benzamide 0.36748 2.26 828_0068_0192

370 [3-[3-(1,3- benzodioxol-5- yl)imidazo[1,2- b]pyridazin-6- yl]phenyl]methanol 0.33166 3.11 828_0068_0291

371 N-[3-[6-(2- thienyl)imidazo [1,2-b]pyridazin- 3-yl]phenyl] acetamide0.20995 3.27 828_0081_4147

372 3-(6- phenylimidazo [1,2-b]pyridazin- 3-yl)phenol 0.89352 3.95828_0284_0061

373 1-[3-[3-(3- hydroxyphenyl) imidazo[1,2- b]pyridazin-6- yl]phenyl]ethanone 1.60026 3.51 828_0284_4145

374 [4-[6-(3- fluorophenyl) imidazo[1,2- b]pyridazin-3- yl]phenyl]methanol 2.95859 3.63 828_0285_0313

375 1-[3-[3-[3- (hydroxymethyl) phenyl]imidazo [1,2-b]pyridazin-6-yl]phenyl] ethanone 2.16824 3.04 828_0291_4145

376 1-[3-[6-[3- (dimethylamino) phenyl]imidazo [1,2-b]pyridazin-3-yl]phenyl] ethanone 0.88623 3.92 828_4145_0135

377 1-[3-[6-(6- amino-3-pyridyl) imidazo[1,2- b]pyridazin-3- yl]phenyl]ethanone 0.28267 2.36 828_4145_7905

378 [4-[3-(2- thienyl)imidazo [1,2-b]pyridazin- 6-yl]phenyl] methanol2.35649 3.26 828_4147_0285

379 N-[3-[3-(3,4- dimethoxyphenyl) imidazo[1,2- b]pyridazin-6-yl]phenyl] methane- sulfonamide 0.70252 2.31 828_0079_6488

380 3-[3-(3- acetylphenyl) imidazo[1,2- b]pyridazin-6- yl]benzamide0.51895 2.66 828_4145_0347

381 N-[3-[3-(3- pyridyl)imidazo [1,2-b]pyridazin- 6-yl]phenyl] methane-sulfonamide 1.41022 1.41 828_0071_6488

382 3-[6-(4- pyridyl)imidazo [1,2-b]pyridazin- 3-yl]phenol 0.20283 2.73828_0284_0069

383 3-[6-(5- quinolyl)imidazo [1,2-b]pyridazin- 3-yl]phenol 14.636384.11 828_0284_6831

384 N-[3-[3-[3- hydroxymethyl) phenyl]imidazo [1,2-b]pyridazin-6-yl]phenyl] methane- sulfonamide 1.15032 1.86 828_0291_6488

385 2-methoxy-4-[6- (2-methoxy- phenyl) imidazo[1,2- b]pyridazin-3-yl]phenol 0.95886 3.63 828_0314_0083

386 3-[3-(3- acetylphenyl) imidazo[1,2- b]pyridazin-6- yl]-N-methyl-benzamide 1.71793 2.89 828_4145_7965

387 [3-[3-(2- thienyl)imidazo [1,2-b]pyridazin- 6-yl]phenyl] methanol1.68324 3.26 828_4147_0291

388 6-(1- methylpyrazol-4- yl)-3-(2- thienyl)imidazo [1,2-b]pyridazine1.3135 2.46 828_4147_7468

389 3-[3-(3,4- dimethoxyphenyl) imidazo[1,2- a]pyridazin-6-yl]- N-(2-hydroxyethyl) benzamide 0.3666 2.32 828_0079_0192

390 3-(1,3- benzodioxol-5- yl)-6-(1- methylpyrazol-4- yl)imidazo[1,2-b]pyridazine 0.95557 2.30 828_0068_7468

391 3-(3,4- dimethoxy- phenyl)-6-(1- methylpyrazol-4- yl)imidazo[1,2-b]pyridazine 0.36693 2.37 828_0079_7468

392 3-[6-(3- fluorophenyl) imidazo[1,2- b]pyridazin-3- yl]phenol 2.264414.09 828_0284_0313

393 1-[3-[6-(3- aminophenyl) imidazo[1,2- b]pyridazin-3- yl]phenyl]ethanone 1.12246 2.98 828_4145_0005

394 6-(2-methoxy- phenyl)-3-(3- pyridyl)imidazo [1,2-b]pyridazine 2.35032.88 828_0071_0083

395 3-(3,4- dimethoxy- phenyl)-6-(4- pyridyl)imidazo [1,2-b]pyridazine0.40386 2.72 828_0079_0069

396 3-[6-(3- pyridyl)imidazo [1,2-b]pyridazin- 3-yl]phenol 0.58643 2.73828_0284_0071

397 3-[6-(1- methylpyrazol-4- yl)imidazo[1,2- b]pyridazin-3- yl]phenol0.38762 2.38 828_0284_7468

398 [4-[6-(4- fluorophenyl) imidazo[1,2- 3]pyridazin-3- yl]phenyl]methanol 2.94383 3.63 828_0285_0339

399 4-[6-(3- hydroxyphenyl) imidazo[1,2- b]pyridazin-3- yl]-2-methoxy-phenol 0.29478 3.49 828_0314_0284

400 6-(3,4- dimethoxy- phenyl)-3-(4- pyridyl)imidazo [1,2-b]pyridazine0.28231 2.72 828_0069_0079

401 6-(4- fluorophenyl)-3- (3- pyridyl)imidazo [1,2-b]pyridazine 2.778763.18 828_0071_0339

402 [3-[3-(3- chlorophenyl) imidazo[1,2- b]pyridazin-6- yl]phenyl]methanol 9.81893 4.09 828_0279_0291

403 3-[6-(4- fluorophenyl) imidazo[1,2- b]pyridazin-3- yl]phenol11.87843 4.09 828_0284_0339

404 3-phenyl-6-(2- thienyl)imidazo [1,2-b]pyridazine 1.9697 4.03828_0061_4147

405 3-(3,4- dimethoxy- phenyl)-6-(3- pyridyl)imidazo [1,2-b]pyridazine0.54944 2.72 828_0079_0071

406 N-[3-[3-(3- hydroxyphenyl) imidazo[1,2- b]pyridazin-6- yl]phenyl]acetamide 1.64512 3.19 828_0284_0081

407 4-[6-[4- (hydroxymethyl) phenyl]imidazo [1,2-b]pyridazin-3-yl]-2-methoxy- phenol 0.12455 3.02 828_0314_0285

408 3-[3-(3,4- dimethoxyphenyl) imidazo[1,2- b]pyridazin-6-yl]-N-methyl- benzamide 3.49397 3.01 828_0079_7965

409 N-[3-[3-(4- pyridyl)imidazo [1,2-b]pyridazin- 6-yl]phenyl] acetamide0.59778 2.27 828_0069_0081

410 6-(3-furyl)-3-(3- pyridyl)imidazo [1,2-b]pyridazine 2.34906 2.18828_0071_0343

411 N-[3-[6-(3,4- dimethoxyphenyl) imidazo[1,2- p]pyridazin-3-yl]phenyl] acetamide 0.25932 3.18 828_0081_0079

412 3-[6-(3- furyl)imidazo[1,2- b]pyridazin-3- yl]phenol 1.05684 3.09828_0284_0343

413 1-[3-[6-(4- pyridyl)imidazo [1,2-b]pyridazin- 3-yl]phenyl] ethanone0.37149 2.59 828_4145_0069

414 6-(m- tolylmethyl)-3-(4- pyridyl)imidazo [1,2-b]pyridazine 0.977063.48 828_0069_6291

415 3-(1,3- benzodioxol-5- yl)-6-(4- fluorophenyl) imidazo[1,2-b]pyridazine 7.60066 4.02 828_0068_0339

416 3,6-bis(3,4- dimethoxyphenyl) imidazo[1,2- b]pyridazine 0.53841 3.62828_0079_0079

417 3-[6-(2- methoxyphenyl) imidazo[1,2- b]pyridazin-3- yl]phenol2.73595 3.79 828_0284_0083

418 [4-(6- phenylimidazo [1,2-b]pyridazin- 3-yl)phenyl] methanol 1.458983.49 828_0285_0061

419 N-[4-[3-[4- (hydroxymethyl) phenyl]imidazo [1,2-b]pyridazin-6-yl]phenyl] acetamide 21.45348 2.72 828_0285_0722

420 4-[6-[3- (hydroxymethyl) phenyl]imidazo [1,2-b]pyridazin-3-yl]-2-methoxy- phenol 0.10235 3.02 828_0314_0291

421 1-[3-[6-[3- (hydroxymethyl) phenyl]imidazo [1,2-b]pyridazin-3-yl]phenyl] ethanone 0.17883 3.04 828_4145_0291

422 3-(4-pyridyl)-3- (2- thienyl)imidazo [1,2-b]pyridazine 0.49696 2.81828_4147_0069

423 2-methoxy-4-[3- (2-thienyl) imidazo[1,2-b] pyridazin-6- yl]phenol0.69396 3.57 828_4147_0314

424 N-(2- hydroxyethyl)-3- (3-phenyl- imidazo[1,2-b] pyridazin-6-yl)benzamide 13.86362 2.64 828_0061_0192

425 6-benzyl-3-(4- pyridyl)imidazo [1,2-b]pyridazine 0.6243 2.97828_0069_6001

426 4-[3-(3- pyridyl)imidazo [1,2-b]pyridazin- 6-yl]benzamide 11.243481.89 828_0071_0346

427 1-[3-[6-(3- pyridyl)imidazo [1,2-b]pyridazin- 3-yl]phenyl] ethanone1.23395 2.59 828_4145_0071

428 1-[3-[6-(3- methoxyphenyl) imidazo[1,2- b]pyridazin-3- yl]phenyl]ethanone 1.78495 3.65 828_4145_4140

429 6-[(4- fluorophenyl) methyl]-3-(4- pyridyl)imidazo [1,2-b]pyridazine1.44642 3.11 828_0069_6370

430 3-[3-(1,3- benzodioxol-5- yl)imidazo[1,2- b]pyridazin-6- yl]aniline0.84313 3.05 828_0068_0005

431 3-(1,3- benzodioxol-5- yl)-6-(3-furyl) imidazo[1,2- b]pyridazine1.60154 3.02 828_0068_0343

432 [4-[6-(3,4- dimethoxyphenyl) imidazo[1,2- b]pyridazin-3- yl]phenyl]methanol 3.9402 3.17 828_0285_0079

433 3-[3-(1,3- benzodioxol-5- yl)imidazo[1,2- b]pyridazin-6- yl]-N-(2-dimethylamino- ethyl)benzamide 0.39289 2.97 828_0068_0176

434 N-[3-[6-(3-chloro- 4-fluoro- phenyl)imidazo [1,2-b]pyridazin-3-yl]phenyl] acetamide 0.52521 4.24 828_0081_0164

435 3-[3-[4- (hydroxymethyl) phenyl]imidazo [1,2-b]pyridazin-6-yl]phenol 1.13696 3.18 828_0285_0284

436 [3-[6-(3,4- dimethoxyphenyl) imidazo[1,2- b]pyridazin-3- yl]phenyl]methanol 0.74933 6.29 828_0291_0079

437 1-[3-[3-(3- acetylphenyl) imidazo[1,2- b]pyridazin-6- yl]phenyl]ethanone 0.58173 3.37 828_4145_4145

438 N-(2-dimethyl- aminoethyl)-3- [3-(2-thienyl) imidazo[1,2-b]pyridazin-6- yl]benzamide 1.1611 3.12 828_4147_0176

439 3-(1,3- benzodioxol-5- yl)-6-phenyl- imidazo[1,2- b]pyridazine3.08798 3.88 828_0068_0061

440 3-[3-(3- pyridyl)imidazo [1,2-b]pyridazin- 6-yl]phenol 1.81461 2.73828_0071_0284

441 3-(3,4- dimethoxy- phenyl)-6-(2- thienyl)imidazo [1,2-b]pyridazine0.21139 3.72 828_0079_4147

442 3-[3-(3- hydroxyphenyl) imidazo[1,2- b]pyridazin-6- yl]phenol0.98714 3.65 828_0284_0284

443 N-[3-[3-[4- (hydroxymethyl) phenyl]imidazo [1,2-b]pyridazin-6-yl]phenyl] acetamide 2.2389 2.72 828_0285_0081

444 1-[3-[6-(4- fluorophenyl) imidazo[1,2- b]pyridazin-3- yl]phenyl]ethanone 4.81048 3.95 828_4145_0339

445 3-[3-(3- acetamido- phenyl)imidazo [1,2-b]pyridazin- 6-yl]-N-methyl-benzamide 1.3298 2.57 828_0081_7965

446 [3-(3- phenylimidazo [1,2-b]pyridazin- 6-yl)phenyl] methanol 1.928573.49 828_0061_0291

447 6-(1- methylpyrazol- 4-yl)-3-(4- pyridyl)imidazo [1,2-b]pyridazine30 1.46 828_0069_7468

448 N-(2- dimethylamino- ethyl)-3-[3-[3- (trifluoromethoxy)phenyl]imidazo [1,2-b]pyridazin- 6-yl]benzamide 3.93108 4.78828_0168_0176

449 [4-[3-[4- (hydroxymethyl) phenyl]imidazo [1,2-b]pyridazin-6-yl]phenyl] methanol 1.03522 2.72 828_0285_0285

450 4-[6-(1,3- benzodioxol-5- yl)imidazo[1,2- b]pyridazin-3-yl]-2-methoxy- phenol 0.1999 3.42 828_0314_0068

451 1-[3-[6-(2- thienyl)imidazo [1,2-b]pyridazin- 3-yl]phenyl] ethanone0.41575 3.59 828_4145_4147

452 6-(5-methoxy-3- pyridyl)-3-(2- thienyl)imidazo [1,2-b]pyridazine2.86231 2.66 828_4147_0196

453 3,6-bis(2- thienyl)imidazo [1,2-b]pyridazine 4.89416 3.81828_4147_4147

454 N-(2-dimethyl- aminoethyl)-3- [6-(1-methyl- pyrazol-4-yl)imidazo[1,2- b]pyridazin-3- yl]benzamide 1.76458 1.77 828_0176_7468

455 3-[6-(1,3- benzodioxol-5- yl)imidazo[1,2- b]pyridazin-3- yl]-N-(2-dimethylamino- ethyl)benzamide 2.01862 2.97 828_0176_0068

456 3-[3-[3-(2- dimethylamino- ethylcarbamoyl) phenyl]imidazo[1,2-b]pyridazin- 6-yl]benzamide 4.14881 2.20 828_0176_0347

457 N-(2- hydroxyethyl)-3- [3-(3- hydroxyphenyl) imidazo[1,2-b]pyridazin-6- yl]benzamide 0.35163 2.33 828_0284_0192

458 2-methoxy-4-[6- (3,4,5- trimethoxyphenyl) imidazo[1,2-b]pyridazin-3- yl]phenol 1.81139 3.32 828_0314_0087

459 [3-[3-(3-furyl) imidazo[1,2- b]pyridazin-6- yl]phenyl] methanol7.32807 2.63 828_0343_0291

460 4-(6- benzylimidazo [1,2-b]pyridazin- 3-yl)benzamide 0.71127 3.04828_0346_6001

461 3-[6-(4- acetamidophenyl) imidazo[1,2- b]pyridazin-3- yl]-N-(2-dimethylamino- ethyl)benzamide 0.98309 2.58 828_0176_0722

462 2-methoxy-4-[6- [3-(trifluoro- methoxy)phenyl] imidazo[1,2-b]pyridazin- 3-yl]phenol 0.83451 5.22 828_0314_0168

463 N-(2- dimethylamino- ethyl)-3-[6-[3- (hydroxymethyl) phenyl]imidazo[1,2-b]pyridazin- 3-yl]benzamide 0.81608 2.58 828_0176_0291

464 4-[6-[(3,4- difluorophenyl) methyl]imidazo [1,2-b]pyridazin-3-yl]benzamide 3.07271 3.52 828_0346_6007

465 3-[6-(3- acetamidophenyl) imidazo[1,2- b]pyridazin-3-yl]- N-(2-dimethylamino- ethyl)benzamide 3.16865 2.58 828_0176_0081

466 2-methoxy-4-[6- [3-(trifluoro- methyl)phenyl] imidazo[1,2-b]pyridazin-3- yl]phenol 1.08271 4.67 828_0314_0312

467 6-benzyl-3-(5- methoxy-3- pyridyl)imidazo [1,2-b]pyridazine 2.673062.81 828_0196_6001

468 4-[6-(m- tolylmethyl) imidazo[1,2- b]pyridazin-3- yl]benzamide3.10262 3.55 828_0346_6291

469 N-(2- dimethylamino- ethyl)-3-[6-(2- methoxyphenyl) imidazo[1,2-b]pyridazin-3- yl]benzamide 2.13745 3.19 828_0176_0083

470 N-(2- dimethylamino- ethyl)-3-[6-(3- phenoxyphenyl) imidazo[1,2-b]pyridazin-3- yl]benzamide 19.18297 4.85 828_0176_4032

471 3-(6-cyclo- propylimidazo[1,2- b]pyridazin-3- yl)phenol 1.88565 2.83828_0284_7494

472 4-[6-(3-fluoro- phenyl)imidazo [1,2-b]pyridazin- 3-yl]-2-methoxy-phenol 0.28065 3.93 828_0314_0313

473 6-[(4-fluoro- phenyl)methyl]- 3-(5-methoxy- 3-pyridyl)imidazo[1,2-b]pyridazine 4.41614 2.95 828_0196_6370

474 4-[6-[(4-fluoro- phenyl)methyl] imidazo[1,2- b]pyridazin-3-yl]benzamide 1.30064 3.18 828_0346_6340

475 N-(2- hydroxyethyl)- 3-[3-[4- (hydroxymethyl) phenyl]imidazo[1,2-b]pyridazin- 6-yl]benzamide 2.14389 1.87 828_0285_0192

476 3-[3-(4-hydroxy- 3-methoxy- phenyl)imidazo [1,2-b]pyridazin-6-yl]benzamide 0.22316 2.64 828_0314_0347

477 3-(1- methylpyrazol- 4-yl)-6-(m- tolylmethyl) imidazo[1,2-b]pyridazine 1.79534 3.13 828_7468_6291

478 3-[3-(3- acetylphenyl) imidazo[1,2- b]pyridazin-6- yl]-N-(2-hydroxyethyl) benzamide 0.6293 2.20 828_4145_0192

479 [4-(6- benzylimidazo [1,2-b]pyridazin- 3-yl)phenyl] methanol 3.226753.42 828_0285_6001

480 4-[6-[(4- fluorophenyl) methyl]imidazo [1,2-b]pyridazin-3-yl]-2-methoxy- phenol 2.08974 3.87 828_0314_6370

481 6-[(4- fluorophenyl) methyl]-3-(1- methylpyrazol- 4-yl)imidazo [1,2-b]pyridazine 1.29697 2.76 828_7468_6370

482 N-(2- dimethylamino- ethyl)-3-[6-(4- fluorophenyl) imidazo[1,2-b]pyridazin-3- yl]benzamide 2.23882 3.49 828_0176_0339

483 3-[3-(3- chlorophenyl) imidazo[1,2- b]pyridazin-6- yl]-N-(2-hydroxyethyl) benzamide 30 3.24 828_0279_0192

484 3-[6-(m- tolylmethyl) imidazo[1,2- b]pyridazin-3- yl]benzamide2.16636 3.55 828_0347_6291

485 1-[3-(6- benzylimidazo [1,2-b]pyridazin- 3-yl)phenyl] ethanone3.9717 3.74 828_4145_6001

486 5-(6- benzylimidazo [1,2-b]pyridazin- 3-yl)pyridin-2- amine 3.636372.73 828_7905_6001

487 N-(2- dimethylamino- ethyl)-3-[6-(3- furyl)imidazo [1,2-b]pyridazin-3-yl]benzamide 3.88391 2.49 828_0176_0343

488 3-[3-[4- (hydroxymethyl) phenyl]imidazo [1,2-b]pyridazin-6-yl]-N-methyl- benzamide 14.94149 2.56 828_0285_7965

489 4-[4-[3-(2- methoxyphenyl)- 1H-pyrazolo[3,4- b]pyridin-4- yl]phenyl]morpholine 1.38698 3.86 932_2105_0001

490 4-(3-chloro-4- fluoro-phenyl)- 3-(2-methoxy- phenyl)-1H-pyrazolo[3,4- b]pyridine 1.28108 4.72 932_2105_0164

491 3-(2- methoxyphenyl)- 4-(6-methoxy-3- pyridyl)-1H- pyrazolo[3,4-b]pyridine 2.93037 3.19 932_2105_0311

492 3-(2- methoxyphenyl)- 4-(2-methoxy- pyrimidin-5- yl)-1H-pyrazolo[3,4- b]pyridine 6.43118 2.57 932_2105_7628

493 4-[3-(3- fluorophenyl)- 1H-pyrazolo[3,4- b]pyridin-4-yl]-N,N-dimethyl- benzamide 3.86464 3.57 932_5640_7464

494 N,N-dimethyl-4- [3-(3-thienyl)-1H- pyrazolo[3,4- b]pyridin-4-yl]benzamide 11.19371 3.20 932_2055_7464

495 N-[4-(3- cyclopropyl-1H- pyrazolo[3,4- b]pyridin-4- yl)phenyl]acetamide 8.88989 2.24 932_2070_0722

496 3-[3-(4-pyridyl)- 1H-pyrazolo[3,4- b]pyridin-4- yl]aniline 18.006682.08 932_5650_0005

497 4-[3-(3- fluorophenyl)- 1H-pyrazolo[3,4- b]pyridin-4- yl]phenyl]methanol 3.87681 3.50 932_5640_0285

498 3-(2- methoxyphenyl)- 4-(3-thienyl)-1H- pyrazolo[3,4- b]pyridine2.66842 3.75 932_2105_0074

499 N-[4-[3-(3,4,5- trimethoxy- phenyl)-1H- pyrazolo[3,4- b]pyridin-4-yl]phenyl] acetamide 2.02053 2.89 932_4516_0722

500 3-(2- methoxyphenyl)- 4-[(E)-styryl]-1H- pyrazolo[3,4- b]pyridine1.12832 4.66 932_2105_0170

501 4-(3- fluorophenyl)-3- [2-methoxy- phenyl)-1H- pyrazolo[3,4-b]pyridine 1.35112 4.11 932_2105_0313

502 4-[3-(2- methoxyphenyl)- 1H-pyrazolo[3,4- b]pyridin-4- yl]benzamide1.47616 2.82 932_2105_0346

503 [4-(3-phenyl-1H- pyrazolo[3,4- b]pyridin-4- yl)phenyl] methanol7.10693 3.36 932_2047_0285

504 3-phenyl-4-(1H- pyrazol-4-yl)-1H- pyrazolo[3,4- b]pyridine 0.85242.43 932_2047_7467

505 4-(4- isopropylphenyl)- 3-(3,4,5- trimethoxy- phenyl)-1H-pyrazolo[3,4- b]pyridine 20.88874 4.90 932_4516_0283

506 4-(3- chlorophenyl)-3- cyclopropyl-1H- pyrazolo[3,4- b]pyridine 303.61 932_2070_0279

507 N-(2- dimethylamino- ethyl)-3-[3-(2- methoxyphenyl)-1H-pyrazolo[3,4- b]pyridin-4- yl]benzamide 4.85182 3.06 932_2105_0176

508 [3-[3-(2- methoxyphenyl)- 1H-pyrazolo[3,4- b]pyridin-4- yl]phenyl]methanol 1.66776 3.20 932_2105_0291

509 4-[3-(3- fluorophenyl)- 1H-pyrazolo[3,4- b]pyridin-4- yl]benzamide2.04666 3.12 932_5640_0346

510 4-[3-(4- chlorophenyl)- 1H-pyrazolo[3,4- b]pyridin-4- yl]benzamide5.71214 3.58 932_5666_0346

511 3-[3-(3,4,5- trimethoxy- phenyl)-1H- pyrazolo[3,4- b]pyridin-4-yl]phenol 5.02812 3.35 932_4516_0284

512 1-[3-[3-(4- piperidyl)-1H- pyrazolo[3,4- b]pyridin-4- yl]phenyl]ethanone 19.65771 1.89 932_2802_4145

513 N-[4-[3-(3- thienyl)-1H- pyrazolo[3,4- b]pyridin-4- yl]phenyl]acetamide 4.86579 3.14 932_2055_0722

514 2-methoxy-4-[3- (4-piperidyl)-1H- pyrazolo[3,4- b]pyridin-4-yl]phenol 11.88451 1.87 932_2802_0314

515 N-[3-[3-(3,4,5- trimethoxy- phenyl)-1H- pyrazolo[3,4- b]pyridin-4-yl]phenyl] methane- sulfonamide 12.76436 2.03 932_4516_6488

516 4-(3-furyl)-3-(2- methoxyphenyl)- 1H-pyrazolo[3,4- b]pyridine4.89672 3.11 932_2105_0343

517 3-[3-(1,3- benzodioxol-5- yl)-1H- pyrazolo[3,4- b]pyridin-4-yl]phenol 6.24902 3.45 932_5654_0284

518 4-(3-furyl)-3-(3- pyridyl)-1H- pyrazolo[3,4- b]pyridine 14.298352.05 932_2094_0343

519 [4-[3-(3,4,5- trimethoxy- phenyl)-1H- pyrazolo[3,4- b]pyridin-4-yl]phenyl] methanol 5.38048 2.89 932_4516_0285

520 4-(3- methoxyphenyl)- 3-(4-piperidyl)- 1H-pyrazolo[3,4- b]pyridine17.59629 2.17 932_2802_4140

521 4-[3-(2- methoxyphenyl)- 1H-pyrazolo[3,4- b]pyridin-4-yl]benzonitrile 1.58329 3.82 932_2105_0086

522 N,N-dimethyl-4- [3-(3,4,5- trimethoxy- phenyl)-1H- pyrazolo[3,4-b]pyridin-4- yl]benzamide 11.14532 2.95 932_4516_7464

523 [4-[3-(1,3- benzodioxol-5- yl)-1H- pyrazolo[3,4- b]pyridin-4-yl]phenyl] methanol 4.64328 2.98 932_5654_0285

524 4-(5-fluoro-2- methoxy- phenyl)-3-(4- piperidyl)-1H- pyrazolo[3,4-b]pyridine 11.69312 2.31 932_2802_8363

525 4-(4- methylsulfonyl- phenyl)-3-(3,4,5- trimethoxy- phenyl)-1H-pyrazolo[3,4- b]pyridlne 11.16027 2.49 932_4516_0174

526 [4-[3-(3- chlorophenyl)- 1H-pyrazolo[3,4- b]pyridin-4- yl]phenyl]methanol 6.49611 3.96 932_2049_0285

527 [3-[3-(1,3- benzodioxol-5- yl)-1H- pyrazolo[3,4- b]pyridin-4-yl]phenyl] methanol 3.09057 2.98 932_5654_0291

528 4-(3-furyl)-3- phenyl-1H- pyrazolo[3,4- b]pyridine 8.62504 3.27932_2047_0343

529 4-(6-methoxy-3- pyridyl)-3-(3,4,5- trimethoxy- phenyl)-1H-pyrazolo[3,4- b]pyridine 16.92312 2.87 932_4516_0311

530 3-cyclopropyl-4- (2-furyl)-1H- pyrazolo[3,4- b]pyridine 12.614412.06 932_2070_0142

531 4-(2-furyl)-3-(2- methoxyphenyl)- 1H-pyrazolo[3,4- b]pyridine2.27665 3.03 932_2105_0142

532 [4-[3-(2- methoxyphenyl)- 1H-pyrazolo[3,4- b]pyridin-4- yl]phenyl]methanol 1.10049 3.20 932_2105_0285

533 1-[3-[3-(2- methoxyphenyl)- 1H-pyrazolo[3,4- b]pyridin-4- yl]phenyl]ethanone 6.60309 3.53 932_2105_4145

534 4-(3-furyl)-3-(4- pyridyl)-1H- pyrazolo[3,4- b]pyridine 20.243362.05 932_5650_0343

535 3-[3-(3- fluorophenyl)- 1H-pyrazolo[3,4- b]pyridin-4- yl]aniline15.07442 3.44 932_5640_0005

536 3-(3-phenyl-1H- pyrazolo[3,4- b]pyridin-4- yl)benzamide 11.717382.98 932_2047_0347

537 3-[3-(3,4,5- trimethoxy- phenyl)-1H- pyrazolo[3,4- b]pyridin-4-yl]aniline 14.80741 2.82 932_4516_0005

538 4-(3- fluorophenyl)-3- (3,4,5- trimethoxy- phenyl)-1H- pyrazolo[3,4-b]pyridine 5.22838 3.80 932_4516_0313

539 (E)-3-[3-[5-(3- pyridylmethyl- amino)pyrazolo [1,5-a]pyrimidin-3-yl]phenyl]prop- 2-enoic acid 2.27421 3.04 294_4003_0289

540 3-[6-amino-5- (3,4,5- trimethoxy- phenyl)- 3-pyridyl] benzamide0.44196 2.19 382_0087_0347

541 1-[5-[6-amino- 5-[3-(dimethyl- amino)phenyl]- 3-pyridyl]-2-thienyl]ethanone 3.41528 3.39 382_0135_0066

542 (Z)-5-[6- (methylamino) imidazo[1,2- b]pyridazin-3- yl]pent-4-en-1-ol 31.48029 1.22 437_0299

543 2-methoxy-4-[2- (tetrahydropyran- 4-ylmethyl- amino)imidazo[2,1-b][1,3,4] thiadiazo-5- yl]phenol 2.16407 2.47 699_0243_0314

544 N-[3-[8- acetamido-3- (3,4-dimethoxy- phenyl)imidazo [1,2-a]pyridin-6-yl]phenyl] acetamide 1.59766 2.13 802_0079_0081

545 N-[3-(3- acetylphenyl)- 6-[3-methoxy- phenyl)imidazo [1,2-a]pyridin-8-yl]acetamide 3.05101 2.61 802_4145_4140

546 5-(5-methoxy-3- pyridyl)-N-(4- pyridylmethyl) imidazo[2,1- b][1,3,4]thiadiazol-2- amine 0.93173 1.64 699_0237_0196

547 4-[[5-(3-chloro- 4-fluoro- phenyl)imidazo [2,1-b][1,3,4] thiadiazol-2-yl]amino] cyclohexanol 4.05722 3.67 699_0240_0164

548 4-[2-[[5-(3,4- dimethoxyphenyl) imidazo[2,1-b] [1,3,4]thiadiazol-2-yl]amino] ethyl]benzene- sulfonamide 5.11606 2.81 699_6182_0079

549 N-[3-(3- acetylphenyl)-6- (2,4-dimethoxy- phenyl)imidazo[1,2-a]pyridin-8- yl]acetamide 2.50187 2.45 802_4145_4141

550 5-(3,4- dimethoxy- phenyl)-N- [2-(4-pyridyl) ethyl]imidazo[2,1-b][1,3,4] thiadiazol- 2-amine 3.1387 2.99 699_0039_0079

551 5-(4-pyridyl)-N- (4-pyridylmethyl) imidazo[2,1-b] [1,3,4]thiadiazol-2-amine 2.64747 1.80 699_0237_0069

552 5-(6-methoxy-3- pyridyl)-N-[2-(4- pyridyl)ethyl] imidazo[2,1-b][1,3,4]thiadiazol- 2-amine 2.03015 2.52 699_0039_0311

553 4-[2-[[5-(3- pyridyl)imidazo [2,1-d][1,3,4] thiadiazol-2-yl]amino]ethyl] benzene- sulfonamide 1.87926 1.91 699_6182_0071

554 5-(4- morpholino- phenyl)-N-(2- thienylmethyl) imidazo[2,1-b][1,3,4]thiadiazol- 2-amine 3.82253 4.03 699_0146_0001

555 [4-[2-[(4- methoxyphenyl) methylamino] imidazo[2,1-b][1,3,4]thiadiazol- 5-yl]phenyl] methanol 2.8094 3.31 699_0244_0285

556 5-(4- chlorophenyl)-N- (3- pyridylmethyl) imidazo[2,1-b][1,3,4]thiadiazol- 2-amine 3.65935 3.62 699_4003_0160

557 N-[3-[2-[2-(4- pyridyl)ethyl- amino]imidazo [2,1-b][1,3,4]thiadiazol-5- yl]phenyl] acetamide 1.31627 2.54 699_0039_0081

558 N,N-dimethyl-3- [2-[2-(4- pyridyl)ethyl- amino]imidazo[2,1-b][1,3,4] thiadiazol-5- yl]benzamide 0.72142 2.60 699_0039_0349

559 2-methoxy-4-[2- [(4-methoxy- phenyl)methyl- amino]imidazo[2,1-b][1,3,4] thiadiazol-5- yl]phenol 1.77761 3.61 699_0244_0314

560 5-(6-methoxy-3- pyridyl)-N-(3- pyridylmethyl) imidazo[2,1-b][1,3,4]thiadiazol- 2-amine 2.93804 2.23 699_4003_0311

561 5-(3-chloro-4- fluoro-phenyl)-N- (2-morpholino- ethyl)imidazo[2,1-b][1,3,4] thiadiazol-2- amine 4.81646 3.05 699_0252_0164

562 5-(4-pyridyl)-N- 2-(4- pyridyl)ethyl] imidazo[2,1-b][1,3,4]thiadiazol- 2-amine 2.42663 2.08 699_0039_0069

563 4-[[5-(6-methoxy- 3-pyridyl) imidazo[2,1-b] [1,3,4]thiadiazol-2-yl]amino] cyclohexanol 1.61261 2.14 699_0240_0311

564 1-[5-[2-(2- morpholinoethyl- amino)imidazo [2,1-b][1,3,4]thiadiazol-5- yl]-2-thienyl] ethanone 3 1.77 699_0252_0066

565 N-[3-(3- acetylphenyl)-6- [2-methoxy- phenyl)imidazo [1,2-a]pyridin-8-yl]acetamide 1.58352 2.61 802_4145_0083

566 N-[3-(3-chloro-4- fluoro-phenyl)-6- [3-(methane- sulfonamido)phenyl]imidazo [1,2-a]pyridin- 8-yl]formamide 2.85911 2.28 788_0164_6488

567 5-(4-pyridyl)-N- (2-thienylmethyl) imidazo[2,1-b] [1,3,4]thiadiazol-2-amine 3.61591 2.93 699_0146_0069

568 N-[3-[2- (cyclohexylamino) imidazo[2,1-b] [1,3,4]thiadiazol-5-yl]phenyl] methane- sulfonamide 4.33348 2.68 699_0052_6488

569 3-[2- (isobutylamino) imidazo[2,1-b] [1,3,4]thiadiazol-5-yl]benzamide 1.13221 2.60 699_0149_0347

570 3-[2- (cyclopropyl- methylamino) imidazo[2,1-b] [1,3,4]thiadiazol-5-yl]benzamide 1.94081 2.14 699_4051_0347

571 4-[[5-(3- fluorophenyl) imidazo[2,1-b] [1,3,4]thiadiazol-2-yl]amino] cyclohexanol 2.92063 3.06 699_0240_0313

572 4-[[5-(3,4- dimethoxyphenyl) imidazo[2,1-b] [1,3,4]thiadiazol-2-yl]amino] cyclohexanol 0.48307 2.60 699_0240_0079

573 5-(3-pyridyl)-N- (2-thienylmethyl) imidazo[2,1-b] [1,3,4]thiadiazol-2-amine 1.94173 2.93 699_0146_0071

574 5-(3,4- dimethoxy- phenyl)-N-(4- pyridylmethyl) imidazo[2,1-b][1,3,4]thiadiazol- 2-amine 2.1285 2.70 699_0237_0079

575 N-[6-(4- aminophenyl)-3- (4-fluorophenyl) imidazo[1,2-a] pyridin-8-yl]acetamide 5.25032 2.53 802_0339_7917

576 N-[3-(4- fluorophenyl)-6- (1-methylpyrazol- 4-yl)imidazo[1,2-a]pyridin-8- yl]formamide 8.08703 1.73 788_0339_8400

577 2-amino-1-(3- methoxyphenyl) pyrrolo[3,2- b]quinoxaline-3-carboxamide 1.18486 2.64 DT2012- 0375412

578 N-cyclohexyl-5- (3-fluorophenyl) imidazo[2,1-d] [1,3,4]thiadiazol-2-amine 4.07753 4.45 699_0052_0313

579 N-(2- furylmethyl)-5- (3-pyridyl)imidazo [2,1-a][1,3,4]thiadiazol-2- amine 3.16405 2.07 699_0144_0071

580 N-(2- furylmethyl)-5- (1-methylpyrazol- 4-yl)imidazo [2,1-b][1,3,4]thiadiazol- 2-amine 5.63578 1.72 699_0144_7468

581 5-(5-methoxy-3- pyridyl)-N-(2- thienylmethyl) imidazo[2,1-b][1,3,4]thiadiazol- 2-amine 0.72859 2.77 699_0146_0196

582 5-(3,4- dimethoxy- phenyl)-N- isobutyl-imidazo [2,1-b][1,3,4]thiadiazol-2- amine 2.74508 3.44 699_0149_0079

583 1-[3-[2-(isobutyl- amino)imidazo [2,1-a][1,3,4] thiadiazol-5-yl]phenyl] ethanone 15.11833 3.31 699_0149_4145

584 N-benzyl-5-(3- pyridyl)imidazo [2,1-b][1,3,4] thiadiazol-2- amine0.8393 3.01 699_0232_0071

585 N-benzyl-5-(5- methoxy-3- pyridyl)imidazo [2,1-b][1,3,4] thiadiazol-2-amine 0.34323 2.86 699_0232_0196

586 5-(3-pyridyl)-N- (tetrahydropyran- 4-ylmethyl) imidazo[2,1-b][1,3,4]thiadiazol- 2-amine 4.84876 1.71 699_0243_0071

587 5-(5-methoxy-3- pyridyl)-N- (tetrahydro- pyran-4- ylmethyl)imidazo[2,1-d][1,3,4] thiadiazol- 2-amine 0.38423 1.55 699_0243_0196

588 N-[(4- methoxyphenyl) methyl]-5-(5- methoxy-3- pyridyl)imidazo[2,1-3][1,3,4] thiadiazol- 2-amine 9.65333 2.70 699_0244_0196

589 N-(o-tolylmethyl)- 5-(3-pyridyl) imidazo[2,1-b] [1,3,4]thiadiazol-2-amine 1.07729 3.53 699_8074_0071

590 1-methyl-N-[4-(4- methylpiperazin- 1-yl)phenyl]-2-[3-(trifluoromethyl) phenyl]pyrrolo [3,2-c]pyridin-6- amine 30 5.51809_2669_5837_0091

591 1-methyl-N- pyrimidin-4-yl- 2-[3-(trifluoro- methyl)phenyl]pyrrolo[3,2- c]pyridin-6- amine 16.77669 4.23 809_2669_5837_6410

592 2-(3- fluorophenyl)-1- methyl-N-[4-(4- methylpiperazin- 1-yl)phenyl]pyrrolo[3,2- c]pyridin-6- amine 12.86554 4.78 809_2670_5837_0091

593 2-(3- fluorophenyl)-1- methyl-N- pyrimidin-4-yl- pyrrolo[3,2-c]pyridin-6- amine 9.08728 3.49 809_2670_5837_6410

594 5-amino-4-(1H- benzimidazol-2- yl)-1-(1,3- benzodioxol-5-yl)-2H-pyrrol-3- one 4.06818 2.64 DT2009- 0160159

595 N,N-dimethyl-4- [4-[4-(4- methylpiperazin- 1-yl)anilino]-1H-pyrrolo[3,2- c]pyridin-2- yl]benzamide 7.04339 3.71 838_2671_0263_0091

596 4-[2-(3,5- dimethoxy- phenyl)-1H- pyrrolo[3,2- c]pyridin-4-yl]morpholine 30 2.59 838_2728_0263_4009

597 N-[4-[[2-(2- methoxyphenyl)- 1H-pyrrolo[3,2- c]pyridin-4-yl]amino]phenyl] acetamide 30 3.54 838_2729_0263_0023

598 2-(2- methoxyphenyl)- 1-methyl-N-[3- (trifluoromethyl)phenyl]pyrrolo [3,2-c]pyridin-4- amine 30 5.40 838_2729_5837_0235

599 8-(2,5-dimethoxy- phenyl)-7-(4- fluorophenyl)-1- methyl-3H-imidazo[1,2-g]purine-2,4- dione [Also listed as: 6-(2,5-dimethoxy-phenyl)-7-(4- fluorophenyl)-4- methyl-purino[7,8- a]imidazole-1,3-dione: 18.44433 2.44 DT2012- 0296118 600 methyl 2-amino- 1-(3-hydroxy-phenyl)pyrrolo [3,2-b]quinoxaline- 3-carboxylate 2.25787 3.64 DT2012-0351552

TABLE 4 Secondary screen- initial candidate compounds re-synthesized andexpanded. logP Compound ID. IUPAC IC50 FYN (con- (prior ID Structurename (μM) sensus) No. if any)

1 5-phenyl-3- (3,4,5- trimethoxy- phenyl)- pyridin- 2-amine 1.30619324823.34 BF000312489 (382_0087_0061)

2 5-[4-(4- methyl- piperazin- 1-yl)phenyl]- 3-(3,4,5- trimethoxy-phenyl)- pyridin- 2-amine 0.232041699 3.30 BF000312520 (382_0087_0218)

3 3-[6-amino- 5-(3,4,5- trimethoxy- phenyl)-3- pyridyl]- phenol0.525870963 3.04 BF000312527 (382_0087_0284)

4 3-[6-amino- 5-(3,4,5- trimethoxy- phenyl)-3- pyridyl]- benzamide0.4942965 2.19 BF000312539 (382_0087_0347)

5 4-[6-amino- 5-(3,4,5- trimethoxy- phenyl)-3- pyridyl]- benzamide0.45785952 2.19 BF000312540 (382_0087_0346)

6 3-[6-amino- 5-(3,4,5- trimethoxy- phenyl)-3- pyridyl]-N- (2- hydroxy-ethyl)- benzamide 1.001189887 1.73 BF000312542 (382_0087_0192)

7 5-(4- methyl- sulfonyl- phenyl)- 3-(3,4,5- trimethoxy- phenyl)-pyridin- 2-amine 0.674160478 2.18 BF000312544

8 N-[3-[6- amino-5- (3,4,5- trimethoxy- phenyl)-3- pyridyl]- phenyl]-methane- sulfonamide 0.561599306 1.72 BF000312545 (382_0087_6488)

9 4-[2-amino- 5-(3,4,5- trimethoxy- phenyl)-3- pyridyl]- phenol 0.28853.04 BF000313556 (382_7249_0087)

10 4-[6-amino- 5-(4- hydroxy- phenyl)-3- pyridyl]- benzamide 1.0856538262.36 BF000313559

11 N-[3-[6- amino-5-(4- hydroxy- phenyl)-3- pyridyl]- phenyl]- acetamide0.898083782 2.75 BF000313562 (382_7249_0081)

12 4-[2-amino- 5-(4-methyl- sulfonyl- phenyl)-3- pyridyl)- phenol1.551309576 2.35 BF000313563 (382_7249_0174)

13 N-[3- (dimethyl- amino)- propyl]- 4-[3-(4- hydroxy- phenyl)-imidazo[1,2- a]pyrazin- 6-yl]- benzamide 0.705417706 1.99 BF000333874

14 4-[6-[4-(4- methyl- piperazin-1- yl)phenyl]- imidazo[1,2-a]pyrazin-3- yl]phenol 0.464568962 2.79 BF000333878 (388_0080_0218)

15 N-[2- (dimethyl- amino)- ethyl]-4- [3-(4-hydroxy- phenyl)-imidazo[1,2- a]pyrazin- 6-yl]- benzamide 0.486180008 1.93 BF000333881

16 N-(2- hydroxy- ethyl)-4-[3- (4-hydroxy- phenyl)- imidazo[1,2-a]pyrazin-6- yl]benzamide 0.739736615 1.22 BF000333882 (388_0080_0328)

17 N-[3- (dimethyl- amino)- propyl]- 4-[3-(4- hydroxy-3- methoxy-phenyl)- imidazo[1,2- a]pyrazin-6- yl]benzamide 0.647432877 1.83BF000334019 (388_0314_0180)

18 N-(2- hydroxy- ethyl)-3-[3-(4- hydroxy-3- methoxy- phenyl)-imidazo[1,2- a]pyrazin-6- yl]benzamide 1.275657607 1.07 BF000334020(388_0314_0192)

19 4-[2-amino- 5-[4-(4- methyl- piperazin-1- yl)phenyl]- 3-pyridyl]-phenol 0.520622627 3.47 BF000710044

20 3-[2-(cyclo- propyl- methyl- amino)- imidazo[2, 1-b][1,3,4]-thiadiazol- 5-yl]-N,N- dimethyl- benzamide 0.884088514 2.59 BF000714798(699_4051_0349)

21 5-(5- methoxy-3- pyridyl)-N- (2-thienyl- methyl)- imidazo[2,1-b][1,3,4]- thiadiazol-2- amine 0.437195357 2.77 BF000714968(699_0146_0196)

22 4-[[5-(3,4- dimethoxy- phenyl)- imidazo[2,1- b][1,3,4]- thiadiazol-2-yl]amino]- cyclohexanol 0.439583985 2.60 BF000717406 (699_0240_0079)

23 3-[2-[(4- hydroxy- cyclohexyl)- amino]- imidazo[2, 1-b][1,3,4]-thiadiazol- 5-yl]-N,N- dimethyl- benzamide 0.288412517 2.22 BF000717418(699_0240_0349)

24 4-[[5-(5- methoxy-3- pyridyl)- imidazo[2,1- b][1,3,4]- thiadiazol-2-yl]amino]- cyclohexanol 0.300821259 1.54 BF000802724

1 2-methoxy- 4-[6-(propyl- amino)- imidazo[1, 2-b]pyridazin- 3-yl]phenol0.081593995 2.71 BF000147080

2 3-(4-pyridyl)- N-(2-thienyl- methyl)-[1,2- a]pyridazin- 6-amine0.104821372 2.71 BF000145941

3 2-methoxy- 4-[6-(tetra- hydropyran-4- ylamino)- imidazo[1,2-b[pyridazin- 3-yl]phenol 0.112523997 1.79 BF000147168

4 4-[2-amino- 5-(3,4,5- trimethoxy- phenyl)-3- pyridyl]-2- methoxy-phenol 0.115507056 2.88 BF000313035 (382_0314_0087)

5 4-[2-amino- 5-[4-(4- methylpiperazin- 1-yl)phenyl]- 3-pyridyl]-2-methoxy- phenol 0.121074357 3.31 BF000313028

6 2-methoxy- 4-[6-(2- thienyl- methyl- amino)- imidazo[1, 2-b]pyridazin-3-yl]phenol 0.166284575 3.46 BF000145954

7 N-(3-[6-(4- hydroxy-3- methoxy- phenyl)- imidazo[1,2- b]pyridazin-3-yl]phenyl]- acatamide 0.166802816 3.03 BF000726183 (828_0081_0314)

8 4-[6-(3- hydroxy- propylamino)- imdazo[1,2- b]pyridazin- 3-yl]-2-methoxy- phenol 0.205976791 1.20 BF000146250 (229_0248_0314)

9 4-[6-amino- 5-(4-hydroxy- 3-methoxy- phenyl)-3- pyridyl]- benzamide0.214088697 2.20 BF000313038

10 N-propyl-3- (4-pyridyl)- imidazo[1,2- b]pyridazin- 6-amine0.217345163 1.95 BF000147056

11 N-[2- (dimethyl- amino)ethyl]-4- [3-(4- phenoxy- phenyl)-imidazo[1,2- a]pyrazin- 6-yl]- benzamide 0.22160528 3.74 BF000334031

12 2-methoxy- 4-[6-(2- pyridyl- methyl- amino)- imidazo[1,2-b]pyridazin- 3-yl]phenol 0.233047949 2.41 BF000817095

13 N-[3- (dimethyl- amino)- propyl]- 4-[3-(4- phenoxy- phenyl)imidazo[1,2- a]pyrazin-6- yl]benzamide 0.247391087 3.80 BF000816927

14 3-(4- pyridyl)-N- tetrahydro- pyran-4-yl- imidazo[1,2- b]pyridazin-6-amine 0.270083246 1.03 BF000817099

15 3-(3,4- dimethoxy- phenyl)-N- propyl- imidazo[1,2- b]pyridazin-6-amine 0.285138703 2.85 BF000147061 (229_0226_0079)

16 N-(1,3- benzodioxol-5- ylmethyl)-3- (4-pyridyl)- imidazo[1,2-b]pyridazin- 6-amine 0.297126173 2.42 BF000146108 (229_0236_0069)

17 N-[3-[6-(3,4- dimethoxy- phenyl)- imidazo[1,2- a]pyridazin-3-yl]phenyl]- acatamide 0.313364743 3.18 BF000726345 (828_0081_0079)

18 4-[2-amino- 5-(4-methyl- sulfolyl- phenyl)- 3-pyridyl]-2- methoxy-phenol 0.315744691 2.19 BF000313040 (382_0314_0174)

19 N-[2- (dimethyl- amino)ethyl]- 4-[3-(4- hydroxy-3- methoxy- phenyl)-imidazo[1,2- a]pyrazin-6- yl]benzamide 0.336758519 1.77 BF000334023

20 3-(1,3- benzodioxol- 5-yl)-N-(2- pyridyl- methyl)- imidazo[1,2-b]pyridazin- 6-amine 0.354989794 2.50 BF000146330 (229_4007_0068)

21 4-[6-amino- 5-(3,4,5- trimethoxy- phenyl)-3- pyridyl]-N- cyclopropyl-benzamide 0.376810127 2.88 BF000312541 (382_0087_7489)

22 N-[3-[6- (tetra- hydropyran- 4-ylamino)- imidazo[1,2- b]pyridazin-3-yl)phenyl]- acetamide 0.396885185 1.49 BF000146155 (229_0242_0081)

23 1-[3-[6- (propyl- amino)- imidazo[1,2- b]pyridazin- 3-yl]phenyl]-ethanone 0.405532058 2.72 BF000147088 (229_0226_4145)

24 4-[6-[[(1S)- 1-(hydroxy- methyl)-2- methyl- propyl]- amino]-imidazo[1, 2-b]pyridazin- 3-yl]-2- methoxy- phenol 0.44318569 2.44BF000146319

25 1-[3-[6-(2- thienyl- methyl- amino)- imidazo[1,2- b]pyridazin-3-yl]phenyl)- ethanone 0.450916544 3.48 BF000145962 (229_0146_4145)

26 N-(2- hydroxy- ethyl)- 4-[3-(4- phenoxy- phenyl)- imidazo- [1,2-a]-pyrazin-6- yl]benzamide 0.463504693 3.03 BF000334032 (388_1029_0328)

27 3-(3,4- dimethoxy- phenyl)-N- tetrahydro- pyran-4-yl- imidazo[1,2-b]pyridazin- 6-amine 0.479948935 1.93 BF000146153 (229_0242_0079)

28 3-(3,4- dimethoxy- phenyl)-N-(2- pyridyl- methyl)- imidazo[1,2-b]pyridazin- 6-amine 0.494462769 2.56 BF000147233

29 N- tetrahydro- pyran-4-yl-3- (3,4,5- trimethoxy- phenyl)-imidazo[1,2- b]pyridazin- 6-amine 0.503383229 1.78 BF000147394(229_0242_0087)

30 3-[[3-(4- pyridyl)- imidazo[1,2- b]pyridazin- 6-yl]amino]-propan-1-ol 0.538085737 0.44 BF000722253

31 3-[6- (propylamino)- imidazo[1,2- b]pyridazin- 3-yl]phenol 0.592307312.86 BF000147075 (229_0226_0284)

32 2-methoxy- 4-[6-(1- methyl- pyrazol- 4-yl)- imidazo[1,2- a]pyrazin-3-yl]phenol 0.624331939 1.11 BF000333452 (388_0314_8400)

33 (2S)-3- methyl-2- [[3-(4- pyridyl)- imidazo[1,2- b]pyridazin- 6-yl]amino]- butan- 1-ol 0.630941398 1.68 BF000817097

34 1-[3-[6-(3- hydroxy- propyl- amino)- imdazo[1,2- b]pyridazin- 3-yl]phenyl]- ethanone 0.64498853 1.21 BF000817098

35 3-[[3-(1,3- benzodioxol- 5-yl)- imidazo[1,2- b]pyridazin- 6-yl]amino]- propan- 1-ol 0.707789559 1.28 BF000146218 (229_0248_0068)

36 5-[6-(3- (dimethyl- amino)- propoxy]- 3-pyridyl]- 3-(3,4,5-trimethoxy- phenyl)- pyridin- 2-amine 0.709144298 2.64 BF000312521(382_0087_0002)

37 3-(3,4- dimetboxy- phenyl)-N-(2- thienyl- methyl)- imidazo[1,2-b]pyridazin- 6-amine 0.721406376 3.61 BF000146992

38 3-[[3-(3,4- dimethoxy- phenyl)- imidazo[1,2- b]pyridazin-6-yl]-amino]- propan-1-ol 0.72516936 1.34 BF000146224

39 N-[3-[6-(4- pyridyl)- imidazo[1,2- b]pyridazin- 3-yl]phenyl]-acetamide 0.740677454 2.27 BF000817142

40 (2S)-2-[[3- (3,4- dimethoxy- phenyl)- imidazo[1,2- b]pyridazin-yl]amino]- 3-methyl- butan-1-ol 0.742215008 2.59 BF000147413(229_0254_0079)

41 N-[3-[6-[[(1S)-1- (hydroxy- methyl)- 2-methyl- propyl]- amino]-imidazo[1,2- b]pyridazin- 3-yl]- phenyl]acetamide 0.791967537 2.14BF000146300 (229_0254_0081)

42 3-(3-methoxy- phenyl)-N- tetrahydro- pyran-4-yl- imidazo[1,2-b]pyridazin- 6-amine 0.828721524 2.09 BF000146183 (229_0242_4140)

43 3-[3-(4- hydroxy- phenyl)- imidazo[1,2- a]pyrazin-6- yl]-N,N-dimethyl- benzamide 0.870676961 2.14 BF000333343 (388_0080_0349)

44 4-[6-(1,3- benzodioxol-5- ylmethyl- amino)- imidazo[1,2- b]pyridazin-3-yl]-2- methoxy- phenol 1.308570599 3.17 BF000146126

45 3-(3- aminophenyl)- N- tetrahydro- pyran- 4-yl- imidazo[1,2-b]pyridazin- 6-amine 1.423322773 1.42 BF000146142 (229_0242_0005)

46 1-[3-[6-(1,3- benzodioxol-5- ylmethyl- amino)- imidazo[1,2-b]pyridazin- 3-yl]phenyl]- ethanone 3.189566346 3.19 BF000147140

47 N-(1,3- benzodioxol- 5-ylmethyl)-3- [3,4- dimethoxy- phenyl)-imidazo[1,2- b]pyridazin- 6-amine 6.216010093 3.32 BF000146114

4-[2-amino- 5-(4-piperazin- 1-ylphenyl)-3- pyridyl]-2- methoxy- phenol0.060908784 2.93 BF000707279

N-benzyl-5- (3-pyridyl)- imidazo[2,1- b][1,3,4]- thiadiazol-2- amine0.633579663 3.01 BF000714845 (699_0232_0071)

3-[2-(benzyl- amino)- imidazo[2,1- b][1,3,4]- thiadiazol- 5-yl]-N,N-dimethyl- benzamide 1.233285044 3.53 BF000714847 (699_0232_0349)

N-benzyl-5- (5-methoxy- 3-pyridyl)- imidazo[2,1- b][1,3,4]-thiadiazol-2- amine 0.217465905 2.86 BF000714862 (699_0232_0196)

5-(5- methoxy-3- pyridyl)-N- (tetra- hydropyran-4- ylmethyl)-imidazo[2,1- b][1,3,4]- thiadiazol- 2-amine 0.292588141 1.55 BF000714923(699_0243_0196)

N-(1,3- benzodioxol-5- ylmethyl)-5- (5-methoxy- 3-pyridyl)- imidazo[2,1-b][1,3,4]- thiadiazol-2- amine 0.289073347 2.48 BF000714981(699_0236_0196)

N,N- dimethyl-3- [2-(tetra- hydropyran-4- ylmethyl- amino)- imidazo[2,1-b][1,3,4]- thiadiazol-5- yl]benzamide 1.363919415 2.23 BF000715802(699_0243_0349)

3-[2-(1,3- benzodioxol-5- ylmethyl- amino)- imidazo[2,1- b][1,3,4]-thiadiazol-5-yl]- N,N- dimethyl- benzamide 1.925583132 3.15 BF000717214

2-methoxy- 4-[2- (tetrahydro- pyran- 4-ylmethyl- amino)- imidazo[2,1-b][1,3,4]- thiadiazol-5- yl]phenol 0.710456332 2.47 BF000717555(699_0243_0314)

3-[3-[3- hydroxy- methyl)- phenyl]- imidazo[1,2- b]pyridazin-6-yl]phenol 1.166257347 3.18 BF000726195 (828_0291_0284)

N-[3-[3-(3- acetamido- phenyl)- imidazo[1,2- b]pyridazin- 6-yl]phenyl]-acetamide 0.647620035 2.73 BF000726346 (828_0081_0081)

3-[6-(4- pyridyl)- imidazo[1,2- b]pyridazin- 3-yl]phenol 0.3421404972.73 BF000726352 (828_0284_0069)

[3-[6-(4- pyridyl)- imidpzo[1,2- b]pyridazin- 3-yl]phenyl]- methanol0.972914631 2.27 BF000726364

[3-[6-(3,4- dimethoxy- phenyl)- imidazo[1,2- b]pyridazin- 3-yl]phenyl]-methanol 0.892824216 3.17 BF000726366 (828_0291_0079)

N-[3-[3-[3- (hydroxy- methyl) phenyl]- imidazo[1, 2-b]pyridazin-6-yl]phenyl]- acetamide 1.516622765 2.72 BF000726367 (828_0291_0081)

4-[6-(3,4- dimethoxy- phenyl)- imidazo[l,2- b]pyridazin- 3-yl]-2-methoxy- phenol 0.039407867 3.48 BF000726453 (828_0314_0079)

N-[3-[3-(4- hydroxy-3- methoxy- phenyl)- imidazo[1,2- b]pyridazin-6-yl]phenyl]- acetamide 0.103548636 3.03 BF000726454 (828_0314_0081)

1-[3-[6-[3- (hydroxy- methyl)- phenyl]- imidazo[1,2- b]pyridazin-3-yl]phenyl]- ethanone 0.290543095 3.04 BF000726471 (828_4145_0291)

4-[6-[4- (hydroxy- methyl)- phenyl]- imidazo[1, 2-b]pyridazin- 3-yl]-2-methoxy- phenol 0.061804045 3.02 BF000726486 828.0314_0285)

4-[6-[3- (hydroxy- methyl)- phenyl]- imidazo[1, 2-b]pyridazin- 3-yl]-2-methoxy- phenol 0.062959987 3.02 BF000726487 (828_0314_0291)

2-methoxy- 4-[6-(4- pyridyl)- imidazo[1,2- b]pyridazin- 3-yl]phenol0.079413853 2.57 BF000817169

3-(4-pyridyl)- N-(2- pyridyl- methyl)- imidazo[1,2- b]pyridazin- 6-amine0.170100794 1.66 BF000817170

3,5- bis(3,4,5- trimethoxy- phenyl)- pyridin-2- amine 0.08540726 2.87BF000817175

4-[2-amino- 5-[4-4- isopropyl- piperazin-1- yl)phenyl]-3- pyridyl]-2-methoxy- phenol 0.078146017 4.08 BF000817185

4-[3-(4- hydroxy-3- methoxy- phenyl)- imidazo[1,2- b]pyridazin- 6-yl]-2-methoxy- phenol 0.02944792 3.33 BF000817186

[3-[3-[3- (hydroxy- methyl)- phenyl]- imidazo[1, 2-b]pyridazin-6-yl]phenyl]- methanol 0.828494158 2.72 BF000817188

5-(3,4- dimethoxy- phenyl)-N- (tetra- hydropyran-4- ylmethyl)-imidazo[2,1- b][1,3,4]- thiadiazol-2- amine 1.026007749 2.61 BF000817208

N-[3-[6-[3- (hydroxy- methyl)- phenyl]- imidazo[1, 2-b]pyridazin-3-yl]phenyl]- acetamide 0.435155145 2.72 BF000817329

4-[2-amino- 5-(4- morpholino- phenyl)-3- pyridyl]-2- methoxy- phenol0.212232208 3.24 BF000817413

5-[6-amino- 5-[4-(4- methyl- piperazin- 1-yl)phenyl]- 3-pyridyl]-2-methoxy- phenol 9.65 3.31 BF000817418

I claim:
 1. A method of treating a condition associated with Fyn kinaseactivity, said method comprising administering a therapeuticallyeffective amount of at least one compound, or pharmaceuticallyacceptable salt or solvate of the compound to a patient in need thereof,wherein the compound is selected fromN-[3-(dimethyl-amino)-propyl]-4-[3-(4-hydroxy-phenyl)-imidazo[1,2-a]pyrazin-6-yl]-benzamide,N-[2-(dimethyl-amino)-ethyl]-4-[3-(4-hydroxy-phenyl)-imidazo[1,2-a]pyrazin-6-yl]-benzamide,N-(2-hydroxy-ethyl)-4-[3-(4-hydroxy-phenyl)-imidazo[1,2-a]pyrazin-6-yl]benzamide,N-[3-(dimethyl-amino)-propyl]-4-[3-(4-hydroxy-3-methoxy-phenyl)-imidazo[1,2-a]pyrazin-6-yl]benzamide,N-(2-hydroxy-ethyl)-3-[3-(4-hydroxy-3-methoxy-phenyl)-imidazo[1,2-a]pyrazin-6-yl]benzamide,N-[2-(dimethyl-amino)ethyl]-4-[3-(4-phenoxy-phenyl)-imidazo[1,2-a]pyrazin-6-yl]-benzamide,N-[3-(dimethyl-amino)-propyl]-4-[3-(4-phenoxy-phenyl)imidazo[1,2-a]pyrazin-6-yl]benzamide,N-[2-(dimethyl-amino)ethyl]-4-[3-(4-hydroxy-3-methoxy-phenyl)-imidazo[1,2-a]pyrazin-6-yl]benzamide,N-(2-hydroxy-ethyl)-4-[3-(4-phenoxy-phenyl)-imidazo-[1,2-a]-pyrazin-6-yl]benzamide,and3-[3-(4-hydroxy-phenyl)-imidazo[1,2-a]pyrazin-6-yl]-N,N-dimethyl-benzamide,wherein the condition associated with Fyn kinase activity is selectedfrom Type 1 diabetes, Type II diabetes, pre-diabetes, and obesity. 2.The method of claim 1 wherein the compound described in Table 4 of thedescription isN-[3-(dimethylamino)propyl]-4-[3-(4-phenoxyphenyl)imidazo[1,2-a]pyrazin-6-yl]benzamide.3. The method of claim 1 wherein the compound described in Table 4 ofthe description isN-[2-(dimethylamino)ethyl]-4-[3-(4-phenoxyphenyl)imidazo[1,2-a]pyrazin-6-yl]benzamide.
 4. A method of inhibiting the activity ofFyn kinase in a cell or a subject, comprising administering to the cellor subject an effective amount of a compound selected fromN-[3-(dimethyl-amino)-propyl]-4-[3-(4-hydroxy-phenyl)-imidazo[1,2-a]pyrazin-6-yl]-benzamide,N-[2-(dimethyl-amino)-ethyl]-4-[3-(4-hydroxy-phenyl)-imidazo[1,2-a]pyrazin-6-yl]-benzamide,N-(2-hydroxy-ethyl)-4-[3-(4-hydroxy-phenyl)-imidazo[1,2-a]pyrazin-6-yl]benzamide,N-[3-(dimethyl-amino)-propyl]-4-[3-(4-hydroxy-3-methoxy-phenyl)-imidazo[1,2-a]pyrazin-6-yl]benzamide,N-(2-hydroxy-ethyl)-3-[3-(4-hydroxy-3-methoxy-phenyl)-imidazo[1,2-a]pyrazin-6-yl]benzamide,N-[2-(dimethyl-amino)ethyl]-4-[3-(4-phenoxy-phenyl)-imidazo[1,2-a]pyrazin-6-yl]-benzamide,N-[3-(dimethyl-amino)-propyl]-4-[3-(4-phenoxy-phenyl)imidazo[1,2-a]pyrazin-6-yl]benzamide,N-[2-(dimethyl-amino)ethyl]-4-[3-(4-hydroxy-3-methoxy-phenyl)-imidazo[1,2-a]pyrazin-6-yl]benzamide,N-(2-hydroxy-ethyl)-4-[3-(4-phenoxy-phenyl)-imidazo-[1,2-a]-pyrazin-6-yl]benzamide,and3-[3-(4-hydroxy-phenyl)-imidazo[1,2-a]pyrazin-6-yl]-N,N-dimethyl-benzamide,or a pharmaceutically acceptable salt or solvate thereof.
 5. The methodof claim 4, wherein the subject has a disease selected from Type Idiabetes, Type II diabetes, and obesity.